INFECTIOUS DISEASES

Infectious Diseases An infectious disease is a disease

resulting from the presence of pathogenic microbial agents, including viruses, bacteria, fungi, protozoa, multicellular parasites and aberrant proteins known as prions. These pathogens are able to cause disease in animals and plants.

Mechanisms of Viral Injury Once viruses are inside host cells, they can damage

or kill the cells by a number of mechanisms:

1. Direct cytopathic effects: Some viruses kill cells by-

preventing synthesis of host macromolecules (e.g., host cell DNA, RNA, or proteins),

by producing degradative enzymes and toxic proteins, or

by inducing apoptosis

For example, poliovirus inactivates cap-binding protein, which is essential for translation of host cell mRNAs but leaves translation of poliovirus mRNAs unaffected.

Some viruses can stimulate apoptosis by production of proteins that are pro-apoptotic. Viral replication also can trigger apoptosis of host cells by cell-intrinsic mechanisms, such as perturbations of the endoplasmic reticulum during virus assembly, which can activate proteases that mediate apoptosis (caspases).

Mechanisms of Viral Injury (contd.)

2. Antiviral immune responses: Viral proteins on the surface of the host cells may be recognized by the immune system, and the host lymphocytes may attack virus-infected cells. Cytotoxic T lymphocytes (CTLs) are important for defense against viral infections, but CTLs also can be responsible for tissue injury. Acute liver failure during hepatitis B infection may be accelerated by CTL-mediated destruction of infected hepatocytes (a normal response to clear the infection).

Mechanisms of Viral Injury (contd.)

3. Transformation of infected cells into benign or malignant tumor cells: Different oncogenic viruses can stimulate cell growth and survival by a variety of mechanisms, including-

expression of virus-encoded oncogenes, anti-apoptotic strategies, or insertional mutagenesis (in which the

function of host genes is altered by viral genes inserted into the host genome)

Mechanisms of Viral Injury (contd.)

Mechanisms of Bacterial InjuryBacterial damage to host tissues depends

on the ability of the bacteria to adhere to host cells, invade cells and tissues, or deliver toxins. Pathogenic bacteria have virulence genes that encode proteins that confer these properties.

1. Virulence of Intracellular Bacteria Facultative intracellular bacteria infect

either epithelial cells, macrophages or both. The growth of bacteria in cells may allow the bacteria to escape from certain effector mechanisms of the immune response (e.g., antibodies), or it may facilitate spread of the bacteria.

Mechanisms of Bacterial Injury (contd.)

Bacteria have a number of mechanisms for entering host cells. Some bacteria use the host immune response to gain entry into macrophages.

Coating of bacteria with antibodies or the complement protein C3b (opsonization) normally results in phagocytosis of bacteria by macrophages.

Like many bacteria, M. tuberculosis activates the alternative complement pathway, resulting in opsonization with C3b. Once coated with C3b, M. tuberculosis binds to the CR3 complement receptor on macrophages and is endocytosed into the cell.

Mechanisms of Bacterial Injury (contd.)

Within macrophages, most bacteria are killed when the phagosome fuses with an acidic lysosome to form a phagolysosome, but certain bacteria elude this host defense. For example, M. tuberculosis blocks fusion of the lysosome with the phagosome, allowing it to proliferate unchecked within the macrophage.

Mechanisms of Bacterial Injury (contd.)

Gram-negative bacteria use a complex secretion system to enter epithelial cells. This system consists of needle-like structures projecting from the bacterial surface that bind to host cells, form pores in the host cell membrane, and then inject proteins that mediate rearrangement of the cell cytoskeleton, facilitating bacterial entry.

Mechanisms of Bacterial Injury (contd.)

Figure: Molecules on the surface of gram-negative and gram-positive bacteria involved in pathogenesis.

Mechanisms of Bacterial Injury (contd.)

Once in the cytoplasm, bacteria have different strategies for interacting with the host cell. Shigella and E. coli inhibit host protein synthesis, replicate rapidly, and lyse the host cell within 6 hours.

Mechanisms of Bacterial Injury (contd.)

2. Bacterial Toxins

Any bacterial substance that contributes to illness can be considered a toxin. Toxins are classified as

Endotoxins, which are components of the bacterial cell, and

Exotoxins, which are proteins that are secreted by the bacterium

Mechanisms of Bacterial Injury (contd.)

2.1 Bacterial endotoxin: Bacterial endotoxin is a lipopolysaccharide (LPS) that

is a large component of the outer membrane of gram-negative bacteria. LPS is composed of a long-chain fatty acid anchor connected to a core sugar chain, both of which are very similar in all gram-negative bacteria.

The response to bacterial LPS can be both beneficial and harmful to the host. The response is beneficial in that LPS activates protective immunity in several ways, including induction of important cytokines and chemoattractants (chemokines) of the immune system as well as increased expression of co-stimulatory molecules, which enhance T-lymphocyte activation.

Mechanisms of Bacterial Injury (contd.)

However, high levels of LPS are thought to play an important role in septic shock, disseminated intravascular coagulation (DIC), and adult respiratory distress syndrome, mainly through induction of excessive levels of cytokines such as TNF, IL-1, and IL-12.

Mechanisms of Bacterial Injury (contd.)

2.2 Bacterial exotoxins

Exotoxins are secreted proteins that cause cellular injury and disease. They can be classified into broad categories by their site and mechanism of action. These are briefly described below:

A)Enzymes: proteases produced by S. aureus B)Toxins: altering intracellular signaling or regulatory

pathways: ex. A-B toxins by V. cholerae C) Neurotoxins: Neurotoxins produced by Clostridium tetani D) Superantigens: Superantigens are bacterial toxins that

stimulate very large number of T lymphocytes. Ex. Superantigen produced by Streptococcus pyogenes

Mechanisms of Bacterial Injury (contd.)