Immuno Research

7/29/2019 Immuno Research

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Immune Evasion by bacteria

How do bacteria circumvent the immune system?

Obviously, if the immune system successfully recognises, consumes and destroys all of the organisms that are

present in any given infection, then that organism has failed to establish itself in the body, and thus cannotcause disease.

However, the immune system does not always succeed in its task. Often the reason for this failure is that the

invading organism has evolved a strategy for evading or suppressing the hosts immune response to that

organism.

Many different strategies have evolved in different organisms; below is presented a list of some of those

strategies.

Strategies directed against acquired immunity

Molecular mimicry. Organisms that employ this strategy genetically resemble parts of the hosts ownbody. The body is less likely to allow the existence of immune antibodies that act against the bodyitself (i.e. autoimmunity), since that can be highly dangerous to the body. By mimicking the

genetic/chemical makeup of the body, organisms can exist without an immune response beingactivated against them. The bacterium Bacteroides, for example, can avoid evoking an immune

response in mice. There are several bacteria that mimic parts of the human body, but these usually

give rise to an immune response. Since the resultant anibodies act against both the foreign organism

and thebodys own tissues, this has the effect of making the body mount an immune response against

itself. Mycobacterium tuberculosis, Mycobacterium leprae, Treponema pallidum, Mycoplasmapneumoniae are all organisms that causeautoimmunity in humans. Mycobacterium

paratuberculosis has been demonstrated to use this strategy in animals.

Suppression of antibodies. In this strategy, the invading organism employs the strategy: the bestform of defense as attack. The organisms in this category target those cells of the immune system

that specifically react against them. By disabling those cells, the organism prevents the body frommounting an immune response against the invader. Two notable bacteria that suppress the bodies

reaction against them are Mycobacterium leprae, the cause of the disease leprosy,

and Mycobacterium tuberculosis, the cause of the disease tuberculosis. In both cases,

the Interleukin-2 response to the bacteria is reduced. In lepromatous leprosy, it has been shown

that suppressor T cells, taken from the skin lesions caused by the disease, inhibit the responses of

other T cells to Mycobacterium leprae antigens.

Hiding inside cells. Many bacteria avoid an immune response by hiding inside the cells of theimmune system. By doing so, they do not present antigens that will evoke an immune response. Theymultiply inside these cells, and then further invade the body when they are greater in number. Among

the bacteria that use this strategy are Brucella, Listeria, Mycobacterium leprae andMycobacterium

tuberculosis, all of whom infect macrophages, the cells that are normally responsible for destroying

invading bacteria. Mycobacterium leprae can also invade and inhabit cells that are not a part of theimmune system, e.g. skin cells.

By releasing antigen into the bloodstream. Normally, the antigen of an invading organism that isrecognised by the body exists on the cell wall of that organism. Some organisms, however, release

these antigens from their cell walls to float freely in the bloodstream, where eventually they will meet

their antibody, and will bind to them, thus rendering those antibodies ineffective. To provide ananalogy, if the immune system were to recognise only the "face" of an organism, then organisms that

use this strategy not only shed their "faces", but also produce as many "faces" as they can, which act


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as decoys and confuse the immune system. This leaves the rest of the organism freedom to move

about unhindered.

Strategies directed against Phagocytes

As you remember, the Phagocytes, i.e. the Macrophages and Microphages, are the cells responsible for

consuming and destroying invading bacteria. Many microbial strategies for survival involve action againstthe Phagocytes. Strategies include

Inhibiting Chemotaxis. Chemotaxis is the chemical process by which thePhagocytes are led to thesite of infection, so that they can begin their task. Some bacteria, such as Staphylococcus Aureus,

produce toxins which inhibit the movement of Phagocytes, which hinders them in their journey.

Inhibiting Phagocytosis. In order to Phagocytose (i.e. swallow and consume)bacteria, phagocytes must first grip onto the invader, and engulf them. Some bacteria

evade Phagocytosis by not presenting anything for the phagocytes to grip onto.

Killing the Phagocyte. Some bacteria are capable of releasing toxins that are lethal to Phagocytes. Soinstead of the invading bacteria being destroyed, the defending phagocytes are themselves destroyed.

Among the bacteria that are capable of this strategy are Mycobacterium tuberculosis, Streptococcus

pyogenes, some Staphylococci, and Bacillus Anthracis (the bacterium that causes thedisease Anthrax).

Colonising the Phagocyte. This highly successful strategy involves the invading bacteria allowingthemselves to be Phagocytosed, but resisting being killed once they are inside the Phagocyte. Many

types of bacteria use Macrophages as sites of sanctuary, where they can multiply without interference

from other cells of the immune system. As mentioned above, bacteria that use this strategy include

Mycobacterium leprae and Mycobacterium tuberculosis.

The Pathology of Mycobacterial Diseases.

Well known human diseases that are caused by mycobacteria are tuberculosis, caused by Mycobacteriumtuberculosis, and leprosy, caused by Mycobacterium leprae. In common with all mycobacterial diseases

(known as mycobacterioses), these diseases come in two forms, the contained form and the aggressive form,

known as the "polar" forms of the disease.

The Contained form.

The contained form of leprosy is known as tuberculoid leprosy and the contained form of tuberculosis is

simply known as the contained form of tuberculosis. People who suffer from the contained forms of

mycobacterioses are known to mount only a "Cell Mediated Immunity" (CMI) response to the infecting

mycobacterium. This CMI response is activated only by T cells. Sufferers do not mount a "Humoral" response

to the invading mycobacterium.

This most recognisable symptom of the contained form is the formation of Granulomas. Granulomas areformed when an invading mycobacterium, possibly living inside an infected host cell, is surrounded by T cells.

First a layer of CD4 T cells surrounds the mycobacterium, and then a layer of CD8 T cells surrounds the layer

of CD4 T cells. This has the effect of forming a hard lump (known as a "tubercle" in tuberculosis) around themycobacterium, from which it cannot escape to further infect the body. Tissue damage around these

granulomas can be extensive, especially if they occur in highly sensitive areas of the body, such as nerve cells,

or the lymph nodes. If formed in the intestines, they lead to the formation of"strictures", which restrict free
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passage of food through the intestines. In "tuberculoid leprosy" sufferers, these granulomas are seen as

lumps in the skin, and can restrict the flow of blood to extremities (fingers, toes, etc.)

The contained forms of mycobacterioses are characterised by the presence of very few numbers of the

infecting mycobacteria compared to the damage caused.

The Aggressive form.

The aggressive form of leprosy is known as "lepromatous leprosy", and the aggressive form of tuberculosis

is known as "miliary tuberculosis". People who suffer from the aggressive forms of mycobacterioses areknown to mount only a "Humoral" response to the infecting mycobacterium. This Humoral response is

activated only by B cells. They do not mount a "Cell Mediated Immunity" (CMI) response to the invading

mycobacterium.

Common symptoms of the aggressive forms of mycobacterioses are perforation, fistulisation of the infectedorgans and abscess formation. Perforation leads to holes in the infected organs, leading to a breach of the

integrity of body cavities. A fistula is a growth of tissue from one organ to another. For example, a fistula may

connect the intestines to the bladder, or to the external skin of the sufferer. If untreated, miliary tuberculosis

will almost certainly result in the death of the sufferer.

The aggressive forms of mycobacteria are characterised by the presence of large numbers of the infecting

mycobacteria, which rage uncontrolled in the infected host.

Autoimmunity.

A possible cause of these failures of the CMI response or of the humoral response is autoimmunity. Some

proteins (known as antigens) which make up mycobacteria are identical to proteins that exist in the human

body. The immune system uses these antigens to combat infections. Both T cells and B cells recognize

antigens, and form other proteins (antibodies) that bind these antigens, thus rendering them harmless, and they

can then be removed from the body (the antibody-antigen pair is known as an immune complex). If antibodies

are formed to antigens that are identical to human proteins (known as self-reactive antigens), then thoseantibodies will also attack the tissues of the body that contain these antigens. These tissues may be far from the

site of infection. This is how secondary inflammatory symptoms, such as arthritis or uveitis, come about. This

phenomenon is known autoimmunity. In some individuals, the body will not allow such self-reactive

antibodies to exist, because they are harmful to the body, and destroys them. This is known as

an anergy reaction.

A full spectrum of reactions.

In practice, mycobacteriosis patients seldom exhibit the extreme contained or aggressive forms described

above, but exhibit a form that is a hybrid of the two. For example,"borderline leprosy" is a form of leprosy

that exhibits symptoms from both tuberculoid and lepromatous leprosy.

Immunology.

Immunology research, where researchers seek to measure the bodies immune response to various bacterial

antigens, are highly specific. Most research looks for an humoral response or for a CMI response. As can be

seen from the above, a search for a CMI (T cell) response to mycobacterial antigen will show a response insufferers of the contained form, but will show no response in sufferers of the aggressive form. Likewise, a

search for an humoral (B cell) response will show a response in sufferers of the aggressive form, but no
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response in sufferers of the contained form. Statistical analysis of results of such searches, without first

dividing the patients into two groups that represent the different forms, will yield random results.

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Innate immune response

Initial responses in Macrophages and dendritic cells:TLR-2 mediates NFkB, and TNF secretion, and binds to theM. leprae andM. tuberculosis wall (2). Some researchers think that

the effective functioning of TLR-2 is necessary to the development of the less severe tuberculoid leprosy, in contrast to a systemilepromatous disease manifestation (2). In lepromatous leprosy, these studies have shown that a significant number of patients

have a defective TLR-2 receptor, which then prohibits any cellular immune response from starting (2). Such a lack of cellular

immunity apparently causes theM. leprae bacterium to proliferate much more efficiently in the human body (2). TLR-4 may alsoplay a role inM. lepraebinding, but to what extent, researchers are not sure (4). The presence of CD14 on the APC surface

increases cell mediated responses toM. leprae up to two-fold, but is not necessary for the initiation of the signaling cascade. (2).

Studies also show that in lepromatous leprosy, cytokines and chemokines are not released by macrophages - and neither areMHC-I or II significantly expressed (3, 5)! In fact, this inhibition of chemical release may serve instead to enhance bacterial

growth (5).

When macrophages (or dendritic cells) do get activated by infection withM. leprae, a number of receptors and inflammatorymolecules are upregulated. The interleukins IL-1, IL-2 IL-12, and IL-18 (which acts on both NK and T-cells) are expressed

(5). TNF-alpha is secreted in order to activate NK cells (5).

M. leprae induces apoptosis in macrophages in a dose-dependent manner (6). Apparently, this is correlated with high levels ofTNF-alpha, as well as various apoptotic receptors (4). It is thought that this apoptosis helps to inhibit bacterial proliferation of the

mycobacterium since mycobacteria are not efficient at replicating outside of the cell (4). In fact, researchers claim that this maybe one of the main differences between tuberculoid and lepromatous leprosy - this initial clearing of bacterial load throughmacrophage apoptosis (4).

The cell membrane ofM. leprae is highly antigenic, and dendritic cells recognize it readily (6). Upon recognition, the dendritic

cells produce IL-12 (6). MMP II is a protein on the surface ofM. leprae that stimulates expression of HLA-ABC, HLA-DR,
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CD86, and CD83 antigens in dendritic cells, and also induces maturation (6). All of this indicates that MMP-II is the protein

onM. leprae that binds to TLR-2 on the APC surface (6). Studies also show that the expression of CD1 by dendritic cells is also

critical to the activation of T-cells in the later adaptive immune response of the body (7).

The deal is, CD8+ cells are critical to defeatingM. leprae once infection has happened (3). The CD8+ cells go around and kill

anyM. leprae bacteria they can find using perforin and granulysin (3). This is great because they are quite efficient at getting rid

of the bacteria that are killing the macrophages (3). However, the T-cells must first be activatedand that is often done bydendritic cells (3). So far, dendritic cells presenting CD1+, CD83+, and the CD40 ligand have been found in areas ofM.

leprae infection, indicating that they do, in fact, play a significant role in activating T-cell immunity (3).

So far, it is difficult to determine how effective dendritic cells are at activating T-cells specifically duringM. lepraeinfection (3).

Studies have shown that infection withM. leprae downregulates the presentation of both MHC-I and II on the surface of dendriti

cells, in addition to a lack of significant upregulation of either CD83+ or IFN-gamma (3).

Initial Responses in neutrophils and NK cells:Both neutrophils and NK cells are very important in inducing further immune response after infection withM. leprae (1). NK

cells are required to induce IFN-gamma production, which further activates macrophages and dendritic cells (1). NK cells then

help to activate T-cells and promote the differentiation of Th1 cells - a vital part of the defense system againstM. leprae infection

(1). The activity of NK cells at the site of infection is generally used as a determinant of how successful host defense is, as they

serve to both kill infected cells and also heavily activate other members of both the innate and adaptive immune system (1). NK

cells also secrete IL-13, though in smaller amounts compared to T-cells (1). This is interesting, because IL-13 is a known

cytokine inhibitor, and generally stops any further IFN-gamma production - and therefore essentially stops the inflammatory

process (1).

Humoral immunity

Humoral immunity involves the interaction of circulating antibodies in blood serum in addition to the actions

of B-cells as activated by Th2-cytokine profiled T-cells. In other words, humoral immunity involves the

adaptive portion of the immune system response that which takes a period of days to take effect after

infection has begun.

The immunoglobulin complex (1 - Janeway et al, 2005 Figure1-17)

Activation of B-cells:B-cells are only significantly activated during the immune response by the cytokines produced by Th2 T-cells:

specifically, IL-4, Il-5, and Il-10 (2). Furthermore, a Th2-predominant T-cell response implies an ineffectual

immune response to the pathogen and results in a severe, often fatal form of leprosy: lepromatous leprosy. This

is likely because of the mycobacteriums unique lifecycle that requires it to replicate inside host cells instead of


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free in tissue or blood. Having to replicate inside of cells prevents much recognition of the bacterial cell wall

and limits any recognition of infection to somatic cell presentation of bacterial epitopes on MHC-I.

Interaction of B-cells and M . leprae:

There is not much information onM. lepraes interaction with B-cells. It does seem clear, however, that in thespecific case ofM. leprae, B-cell activation does not play a significant role in clearing the bacteria from the

body. As evidenced, IgG and IgM blood serum levels are high during lepromatous leprosy infection, while theimmunoglobulin levels are anywhere from high to undetectable levels during tuberculoid leprosy infection,

depending on the activity of the disease in the specific patient (3). In general, however, this study found that

patients with lepromatous leprosy had a stronger IgG and IgM response than patients with tuberculoid leprosy

(3). This trend is indicative of an unnecessary antibody response, given that the milder tuberculoid leprosy

causes a wide range of reactions, including no immunoglobulin secreted at all (3). During infection ofM.

avium (a mycobacterium related toM. leprae which infects the gastrointestinal tract of cattle), an increasing

humoral immune response to the pathogen is paired with higher bacterial shedding in the feces and eventually

death (4). Researchers further posit that this trend found inM. avium can be applied to similar mycobacterial

infections (4).

Infection withM. avium proved to both lowerantigen-specific B-cell levels and also to raiseunspecific,circulating peripheral B-cells (4). These seemingly contradictory conclusions have not yet been fully described,

and their role in promoting further infection by mycobacteria are not understood (4).

Cellular response:

Cell mediated immunity is the part of the immune response that involves actions of macrophages, natural killer

(NK) cells, activated killer T cells (CD8+), and the actions of various cytokines. Cell mediated immunity is

extremely important during the infection process of M. leprae due to the inability of B-cells to mount auseful immune response to pathogen.

Th1 cellular role:Although Th1 cells are not cytotoxic, they do play a very significant role in cell-mediated immunity. In the

case ofM. leprae, an important facet of an effective immune response is the delineation of T-cells into Th1 and

Th2 cell lines. A Th1-dominant immune response toM. leprae indicates development of tuberculoid leprosy (amilder form of leprosy) (3). Th1 T-cells secrete the cytokines Il-2 and IFN-gamma, which support delayed-

type hypersensitivity to the pathogen (3). The Th1 immune response is thought to be chosen throughcirculation of IFN-gamma and IL-12 (3). Interestingly, IFN-gamma also inhibits the progression of T-cells into

Th2 cells (3).

A Th2-dominant immune response to M. leprae indicates development of lepromatous leprosy, which is

discussed in the section humoral immunity.


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Despite studies that show the importance of a Th1-mediated immune response, studies have shown that up to

50% of patients with various types of leprosy have a mixed cytokine profile, also known as Th0 (3). In this T-cell profile, the cells have not differentiated into Th1 or Th2 cytokine profiles (3). There are a few caveats to

this fact; namely, the aforementioned studies only looked at cytokine profiles from the lymph nodes of patientswith leprosy, and not closer to the site of infection or lesion (3). Previous studies have shown that T-cellsnearer to the actual infection are more likely polarized into the Th1 or Th2 cytokine profile (3).

Macrophage response:SinceM. leprae infects macrophages, their activation proves very important for clearing the bacterial infection.

Macrophages are generally activated by Th1 cells, which activate cell-mediated immunity in general (2). When

the infected macrophages are inactive, M. leprae is able to evade the cellular immune response and replicates

inside of the cell until it bursts. Without any signal from outside sources, macrophages are unable to mount any

significant response to the bacterium, and the infection spreads largely unchecked (2). When activated throughTh1 cells (and the cytokines secreted by them), macrophages then are more likely to apoptose (thereby killing

the residing bacterial load) and also activate their lysosomes to fuse with any phagosomes that might be

harboring bacteria (2).

NK response:A Th1 predominant T-cell response usually indicates early movement of the NK cells to the site of infection(1). However, NK cells are also very active in the early stages on infection, before the adaptive immune system

has time to kick in (1). In each case, NK cells are very effective at fighting M. leprae infection as long as they

are both activated (most likely by Th1 cells) and can recognize the infected macrophages or Schwann cells (2).


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Immune System Evasion

Generally,M. leprae manages to avoid the immune system through its unique lifecycle: by replicating

exclusively inside of macrophages and Schwann cells, most phagocytes and antigen-presenting cells do not

encounter the pathogen. This lack of meeting causes a paucity of immune responsehence,M. leprae staysmainly silent.

However, even when an immune response has begun,M. leprae can often avoid complete clearance by the

immune system. By causing a predominantly Th2 cell response,M. leprae is able to avoid direct interaction

with the immune system by preventing the cells that might recognize infected host cells from being activated

in the first place (3). While a predominantly Th2 cell response only occurs in a fraction of leprosy cases, it is

enough to provide a significant evasion system for the pathogen. These cases provide such an ineffective

immune response that the bacterium is actually able to proliferate significantly more, and usually results in

death (3).

In tuberculoid leprosy, immune system evasion tactics are more specific, and less effective. Specifically,M.

leprae has developed a mechanism to prevent host cell apoptosis by affecting a number of apoptosis-linked

mRNAs (2,4).

Apoptosis Prevention:

M. lepraeis able to upregulate the host macrophages production of Mcl-1, an anti-apoptotic gene (2). In

addition,M. lepraedownregulates the cells expression of the pro-apoptotic genes Bak and Bad (2). When

activated, Bad forms heterodimers with Bcl-x and Bcl-2thus switching their roles from apoptosis preventorsto activators (2). A prevalence of Bad in the cell therefore makes it more prone to apoptosis.

LikeM. tuberculosis (which is a mycobacterium similar toM. leprae that causes tuberculosis),M. leprae is

also able to prevent host macrophage apoptosis in vitro (4). While this may not be the case in vivo, it is an

interesting point that the bacterium is able at least in vitro to affect the sensitivity of the host cell to apoptosis.

The mycobacteria find a way to increase expression of Fas-ligand and decrease expression of the Fas receptoron the surface of the macrophages (4). This allows the macrophage to protect itself against killing by CD8+ T-

cells (3). Fas ligand is usually only expressed by the CD8+ cell itself and recognizes the Fas receptor on

infected cells (3). Therefore, the host macrophages increase of Fas-ligand expression serves to hide it from

recognition by the CD8+ T-cell. By this mechanism,M. leprae may (in vivo) be able to evade immune system

recognition by CD8+ T-cells, thereby avoiding the results of a Th1 predominant response (2).


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Induction of anergy:Similarly,M. leprae infection of dendritic cells causes them to be poor inducers of T-cell activation in vitro (1).

In addition, the study suggested that infected DCs that have not fully matured can induce an anergic state in

the DC where it activates regulatory T-cells instead of CD4+ or CD8+ cells and therefore suppresses any

previously activated specific immune response (1). Again, this study was only conducted in vitro, and it is still

questionable as to whether the trend could be replicated in vivo.

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15-26 Host response to viral pathogens relies heavily on T cells

With intracellular parasites, viruses and some microorganisms, cytotoxic T cells are particularly important. Afteractivation, cytotoxic T cells attacked infected host cells killing them.

The response to a viral infection is quite different from that seen in a bacterial infection. Viral infections are

intracellular for the most part, while the case we described above was extracellular. This has two implications. First,

much of the damage is going to occur inside infected cells. Second, elimination of the infection is going to require

destruction of host cells. Therefore, the immune system needs a method of discriminating virally infected cells from

healthy cells. Fortunately our bodies have just such a mechanism and it involves the MHC I molecules. In general,

cell-mediated immunity is much more important for clearing a viral infection.

Immune response to influenza infection

An immune defense against a viral infection is more dependent on T cells and less dependent on antibodies.

Cytotoxic T cells are important in killing virally infected cells. In step (1) influenza virus enters the cell and begins
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to replicate (2). Viral proteins fill the cytoplasm (3). Most go on to form influenza virus and escape (4). The

presence of viral proteins in the cytoplasm also causes the production of -interferon (5). Some viral proteins are

degraded and end up being displayed in MHC I molecules (6). Passing T c cells will test the MHC I molecule

presenting foreign antigen and a fraction will be activated by it. Activated T c cells are directed to differentiate into

cytotoxic T cells by TH1 cells. Activated cytotoxic T cells then attack other virally infected cells displaying viral

antigens in the MHC I molecules that the T cells react to. Viral antigens are also presented to B cells producing

antibodies in a similar fashion to that described in Section 15-25. These antibodies attack free virus, agglutinating it

and making it available for phagocytosis (9).

Influenza virus is a good example to study because it illustrates many of the salient points of viral infection and is

also an important human pathogen. However, remember that the specific response of the immune system is

dependent upon the particular pathogen. Many of the mechanisms that we describe here come into play in other viral

infections, but the exact response is always unique to the particular viral agent.

Influenza is a very contagious disease that easily spreads through respiratory droplets expelled by infected

individuals. For this example, imagine that an influenza sufferer has just sneezed on their hand and then opened a

door, contaminating the door handle. Another person touching the handle can picked up droplets containing

100,000,000 flu viruses and a subsequent touch can transfer 1,000,000 to the nasal or oral cavity. Some of them then

land at the back of the throat. Again, the low pH and unfriendly environment created by the normal flora and host

proteins cause the vast majority of the viruses to be inactivated. Those that do survive bind to sialic acid-containingproteins or lipids on the surface of throat epithelial cells and enter by receptor-mediated endocytosis. A drop in the

pH of the endosome causes a conformational change in the virus and the release of the eight genomic fragments of

influenza virus into the cell. Up until this point, the immune system has no indication that anything is amiss.

Virus begins to replicate and viral proteins accumulate in the infected cell. Some of these proteins are degraded by

host cell machinery and the peptide fragments are transported into the endoplasmic reticulum, where they combine

with newly synthesized MHC I molecules. The MHC I molecules loaded with foreign viral antigens now find their

way to the surface of the cell. The infected cell also begins to produce and secrete -interferon. This notifies

surrounding cells of viral infection and induces them to produce compounds that interfere with viral replication

making further infection more difficult.

Virally infected cells begin to release flu virus particles into the surrounding tissues. The presence of viral particles

and the death of virally infected cells begin the process of inflammation as described forS. pyogenes infection. Thiscauses the characteristic redness, soreness and swelling in the back of the throat and the induction of fever observed

in influenza. At this point, macrophages and dendritic cells take up viruses and viral debris, process them and add to

MHC II molecules for presentation to T helper cells. T H1 cells detect the presented antigen and those that match are

activated and begin to secrete IL-2, which has several effects on other T and B cells responding to the infection.

Mucous secretion from the intensifying inflammation begins to cause a runny nose and coughing. The release of

interferon and IL1 contribute to the aches and fever associated with influenza. As the concentration of virus

increases in the body, these symptoms intensify.

Cytotoxic T cells (Tc cells) roaming in the tissues encounter infected cells presenting viral antigens in their MHC I

molecules. Those that have TCRs that respond to the antigen are activated to begin clonal expansion and develop

into active cytotoxic cells under the influence of the T H1 cells. During the next encounter with a virally infected cell,

these cells again recognize the viral antigen being presented in an MHC I molecule using their TCR, but this time,they are activated to attack the cell. The T c cell binds to the infected cell and begins a destructive cycle. A number of

cytokines, including -interferon and tumor necrosis factor (TNF), are secreted by the T c cell. These factors limit

viral replication in the target cell and also attract phagocytes to the area. The T c cells also produce molecules that

elicit a form of programmed cell death (apoptosis) in the target cell, essentially telling the cell to kill itself.

Phagocytes that enter the area then clean up any remaining viral debris. As in the case of B cells, some of the

Tc cells of the clonal expansion do not differentiate, but remain as memory cells in preparation for the next viral

challenge by this viral strain.


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Phagocytized virus is also presented to TH2 cells that respond by activating in a manner identical to that described

earlier for bacterial infections. Virally infected cells also stimulate B cells that respond by clonal expansion and

differentiation into plasma cells, resulting in the formation of antibodies against viral antigens. Antibodies are

commonly raised against hemagglutinin and neuraminidase, two proteins on the outer surface of the virus. In most

viral infections, antibody is not as important as in bacterial infections, but it does have several consequences.

Antibodies bound to virus cause them to agglutinate, precipitate them out of solution and slow their spread through

the body. Many effective antibodies block the receptor site of the virus and prevent its attachment to new host cells.

These types of antibodies are especially useful in stopping subsequent infections by the same virus. Antibodies

attached to virus also assist phagocytes in the efficient uptake of viral particles.

Free virus in the body is eliminated by the action of antibodies and phagocytes and the activated T c cells destroy any

virally infected cells. As the load of virus present in the body decreases, T suppressor cells help the immune

response abate. After infection, subsequent attack by this strain of influenza virus is prevented by the action of T and

B memory cells.

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rinter

THE IMMUNE SYSTEM AND PARASITIC EVASION

Throughout the course of evolution, parasitic organisms have developed several methods to alter theirenvironments so that they may survive and reproduce, thereby ensuring their propagation. Theseadaptive strategies can be passive or may involve active manipulation of the host's immune systemthrough evasion, exploitation, and molecular piracy. The particular mechanisms used depend on theparasites:

life-cycle stage route of penetration microenvironment in which it is established inside the host (4)

Using Leishmania as our model parasite, we will discuss several such paradigms of parasitic immuneevasion. Specifically, we will compare the intracellular evasion mechanisms of inhibition of

phagosome-lysosome fusion, expression of MHC-I and II molecules, and peptide loading along withprevention of apoptosis to the extracellular mechanism of complement lysis evasion.

The host's mechanisms of defense against parasites range from the relatively simple primary barrierto more elaborate mechanisms that involve a variety of cells and molecules capable of specificrecognition and elimination of pathogens (6). Following penetration of a physical barrier (the body'sfirst layer of protection), the innate immune system generates an immediate but non-specificresponse. This can include the mobilization of immune cells by the production of cytokines; activationof the complement cascade to identify the invader, activate immune cells, and promote the clearanceof dead cells and antibody complexes; identification and removal by white blood cells; and, ifunsuccessful in eliminating the pathogen, activation of the adaptive immune system via antigenpresentation. In the adaptive immune response, the pathogen is identified as non-self during antigenpresentation, and this generates specific responses that are tailored to maximally eliminate the

pathogen itself or cells it has infected. This results in the development of immunological memory sothat future attacks are met with a stronger, faster immune response (7).

EXTRACELLULAR EVASION OF THE HUMORAL IMMUNE RESPONSEThe extracellular portion of the Leishmania life cycle focuses on the transition from the promastigotestage (existing in the sandfly vector and outside of the host macrophage) to the amastigote stage(existing inside the host macrophage) (8). After entering the human host during the blood meal of afemale sandfly, Leishmaniapromastigotes must first evade complement-mediated lysis in thebloodstream until they are engulfed by a macrophage (9). The promastigotes are considered
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part of the extracellular phase ofLeishmania because they have not yet developed into intracellularamastigotes. At this point, the parasite is exposed to the potentially lethal effects of the complementsystem.

In normal humoral immune system functioning, the complement system functions to pierce the cellmembrane of a pathogen, leading to its lysis. It consists of the membrane attack complex (MAC),which is made up of complement proteins. (Each protein begins with C followed by a number reflectingtheir order of discovery.) The MAC must first be assembled and activated before it can attack invaders,and this can be done in one of two waysthe classical pathway or the alternative pathway. In eachpathway, complement proteins are activated by successive cleavages and ultimately result in theformation of the MAC. The MAC is composed of C5b-8 and acts as a receptor for membrane-disruptingC9 molecules. When C5b-8 and poly-C9 bind, the MAC forms a transmembrane pore that leads to thelysis of the target cell (10).

In classical activation, complement proteins are activated by antibodies. Conversely, in the alternativepathway a variety of antigens and components of viruses or other pathogens activate complementproteins. Following complement pathway activation via the alternative pathway, MHC is also then ableto insert into a pathogens cellular membrane and destroy it. Whichever pathway is used to activatethe MAC, this system is essential for fighting off foreign invaders.

The Leishmania parasite has devised a way to evade complement lysis so that it may go on and infectmacrophages. Several hypotheses have been suggested to explain the exact mechanism. In general,each proposed mechanism prevents the proper functioning of the MAC complex, albeit at differentpoints in the activation cascade.Most research supports the theory that lysis evasion depends on the differentiation of promastigotes

into metacyclic forms in the sandfly, which are resistant to complement. However, this mechanism isspecific to the Leishmania majorspecies, where procyclic promastigotes are unable to resistcomplement action.

Furthermore, when insect-stage procyclic promastigotes develop into infective metacyclicpromastigote forms, their membrane is altered to prevent insertion. The major surface molecule of thepromastigote, the lipophosphoglycan (LPG) is expressed on the parasite surface at this time and isconsidered a possible barrier for the insertion of the MAC C5b-C9 subunits into the parasite surfacemembrane because it is approximately twice as long as the form on procyclic promastigotes (11).Alternatively, development into the metacyclic form is associated with changes in membranecarbohydrates, altered motility, and enzyme activities (12). The metacyclic forms are thus highlyactive and are larger in size because they have more protein and less carbohydrate, which couldexplain why it differs from the procyclic promastigote in complement reaction.

A different mechanism specific to Leishmania donovanipromastigotes is the prevention of C5convertase formation by fixing the inactive C3bi subunit on their surfaces (9). The surface glycoproteingp63, a protease, has been reported to protect Leishmania amazonensis and Leishmaniamajoragainst cellular lysis by converting C3b into C3bi, thus favoring parasite opsonization.Opsonization makes the parasite more susceptible to phagocytosis and thus less vulnerable tocomplement (9).

Interestingly, Leishmania also exploits the complement system to increase its infectivity of host cells.It uses complement activation as a means to be phagocytized by a macrophage. Unlike otherparasites such as Toxoplasma gondii, Leishmania does not use a specific receptor on the host cell togain entry and is instead passively taken up by macrophages. It relies on complement proteins andantibody to coat its surface, which then leads to opsonizationthe ability of macrophages to take upopsonized (antibody-coated) particles (7). By subverting the complement system and exploiting it as ameans for host cell entrance, Leishmania is able to persist within its extracellular environment.


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INTRACELLULAR EVASION OF THE CELL-MEDIATED RESPONSE

As mentioned earlier, Leishmania lives primarily in macrophages. Macrophages are derived from whiteblood cells and are found in the tissues. Their role is to clear cellular debris and pathogens from thebody through phagocytosis. In normal cellular immune system functioning, the macrophage ingests aparasite into a phagosome, which fuses to one of the cell's many late endosomes and lysosomes.Parasite proteins are then degraded into short peptide fragments, which the macrophage thenpresents in the context of MHC class II molecules to CD4+ helper T cells, another type of white bloodcell, in the lymph node. Macrophages may also display parasite peptides in the context of MHC class Imolecules to CD8+ cytotoxic T cells. This activates the cytotoxic T cells to proliferate and destroy theinfected macrophage through the secretion of the cytokine interferon gamma (IFN-g) (7).

Alan Sher of the National Institute of Health notes that "it's kind of ironic that Leishmania decides tolive in the most dangerous cell in the body (3). It is only able to do so, however, by manipulating themacrophage's machinery in various ways. Most notably, Leishmania inhibits the macrophage

proteolytic process by preventing the fusion of its own parasitophorous vacuole (a nonfusigenicversion of a phagosome that lacks important host surface proteins) with the cell's lysosomes. LPG,which has been previously mentioned in the extracellular evasion of complement, is imperative in thisprocess as well. Studies have confirmed that the LPG surface protein becomes incorporated into thephagosome membrane and somehow inhibits parasitophorous vacuole fusion with endosomes, in spite

of the fact that the host cell fusion machinery remains operational during infection (14). The exactmechanism by which LPG prevents phagosome-endosome fusion is not known.

LPG is also implicated in the prevention of apoptosis by Leishmania-infected macrophages. Apoptosisis a signal-dependent physiologic suicide mechanism that allows for the homeostatic balance betweencell proliferation and cell death. It involves the transcription of specific genes and requires a triggerfrom the environment, usually exposure to or the removal of a specific growth factor or hormone. Ithas been shown that LPG inhibits apoptosis in bone marrow macrophages in vitro and that theparasite also induces the expression of a number of cytokine genes (15). Therefore it is thought that

with the help of LPG, Leishmania-mediated inhibition of apoptosis may be related to the stimulation ofcellular cytokine gene expression. Specifically, the cytokine TNF a is induced in infected cells, and actsin an autocrine manner to inhibit apoptosis with the help of additional factors such as LPG. However, ifthe phagolysosome does form, another parasitic surface protein, gp63, inhibits degradativephagolysosomal enzymes (16). This also ensures the survival of the parasite within the host cell.

Lastly, Leishmania promotes its survival within the macrophage by down regulating MHC moleculesand by preventing their antigen presentation. The glycosylinositolphospholipid Leishmania component

has been found to prevent the expression of both classes of MHC molecules. The degree of genesuppression correlates with both the duration of infection and the parasitic load (17). This is supportedby the fact that increasing quantities of IFN-g do not remedy this. (Recall that IFN-g stimulatesinfected macrophages to die.) For the few MHC molecules that are produced, however, the parasite isable to prevent peptide loading. Gp63 cleaves the CD4+ molecules on T cells, undermining theinteraction between antigen-presenting cells and T helper cells (18). One hypothesized mechanisminvolves the release of proteolytic enzymes by the parasite in the vicinity of peptide loading onto theMHC molecules, essentially degrading the peptides "on the spot" (19). Thus, Leishmania is capable ofsubverting key macrophage accessory functions that are required for the induction of T cell-dependentanti-parasite immunity.

http://www.stanford.edu/class/humbio153/ImmuneEvasion/Background.html

Streptococcus Pneumoniae

Streptococcus pneumoniae is a human pathogen that frequently causes pneumonia, otitis media,

septicemia, and meningitis (47). The mucosal epithelium of the nasopharynx is the primary site of
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colonization, and individuals can carry up to four different serotypes asymptomatically(63). In some

cases, perhaps in conjunction with a viral infection, the host is predisposed to symptomatic

pneumococcal infections including sinusitis, otitis media, and pneumonia. In rare cases, sepsis

develops and seeds infections at distant sites (e.g., meningitis).

Recent studies of the natural course of disease progression have suggested that pneumococcaladherence to mucosal surfaces involves cytokine-mediated upregulation of platelet-activating factor

receptor (63). However, there remain considerable gaps in our understanding of the mechanism of

pneumococcal invasion of host tissue. Identification of the molecules important in the disease

progression has become easier with the development of mouse models of pneumococcal diseases that

replicate nasopharyngeal colonization that can lead to pneumonia and sepsis (67).

Host defense againstS. pneumoniae involves mainly acute-phase responses as well as antibodies to

pneumococcal antigens. C-reactive protein is an acute-phase protein that binds to phosphocholine

moieties within cell wall polysaccharide (C-PS) in the presence of calcium (65). C-reactive protein

promotes phagocytosis ofS. pneumoniae by human leukocytes (34) and protects mice against fatalpneumococcal infection (60, 71). Either short-term or chronic ablation of tumor necrosis factor and

tumor necrosis factor receptor (TNF/TNFR) function renders mice more susceptible toS.

pneumoniae, suggesting that cytokine-mediated inflammatory processes play an integral role in host

defense against pneumococcal infection (50, 61). Classic studies demonstrated that antibodies to

capsular polysaccharide (Caps-PS) are an important component of the adaptive immune response to

pneumococcal infection (38). Subsequent studies, however, revealed that antibodies to C-PS (41),

phosphocholine (5), or pneumococcal proteins (e.g., PspA) (7) can protect mice against

pneumococcal infection. Thus, antibodies to many different pneumococcal antigens could be

important in host defense.

CD40L is critical for humoral responses to T-dependent antigens, whereas antibody responses to

type II T-independent antigens (e.g., TNP-Ficoll) occur independently of CD40L

(22, 23, 25, 33, 51, 69). CD40L also regulates fibroblast (11, 70, 73), epithelial (72), and endothelial

(17, 30, 46, 54) cell function through regulation of adhesion molecule expression and production of

prostaglandins, cytokines, and chemokines. The pivotal role of CD40L in protection from viral

infections (4, 42, 52, 62) and from several, but not all, intracellular pathogens or parasites is well

established (10, 14, 16, 26, 29, 32, 36, 59,74). However, the role of CD40L in protection from

infection with extracellular bacteria is less well understood. A protective humoral response

toBorrelia burgdorferi, the causative agent of Lyme disease, is elicited independently of CD40L (21).

In a recent study, Wu et al. demonstrated that the antiphosphocholine-specific immunoglobulin G(IgG) responses elicited by immunization with a nonencapsulated, nonvirulent variant ofS.

pneumoniae are impaired in T-cell-deficient or CD40L(/)mice (68). The present study was

undertaken to determine whether CD40L is essential for protection from an encapsulated strain ofS.

pneumoniae. The effect of anti-CD40L (MR-1) on humoral responses to pneumococcal antigens as

well as susceptibility to pneumococcal infection was examined.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC97170/
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