Cindy, Steph, and Vincent discuss recent problems with dengue virus vaccine, and a bi-specific monoclonal antibody against Zika virus.
Become a patron of Immune!
On episode #30 of the science show This Week in Microbiology, Vincent, Elio, and Michael review how a toxin from Burkholderia pseudomallei inhibits protein synthesis, and the role of the gut microbiome in modulating insulin resistance in mice lacking an innate immune sensor.
You can find TWiM #30 at microbeworld.org/twim.
The complement system is a collection of blood and cell surface proteins that is a major primary defense and a clearance component of innate and adaptive immune responses. At least 30 different complement proteins act sequentially to produce a wide ranges of activities, from cell lysis to augmentation of the adaptive response. The complement system has four major antimicrobial functions.
Lysis – Polymerization of specific activated complement components on a foreign cell or enveloped virus leads to the formation of pores. The lipid bilayer of the cell or virus is disrupted.
Activation of inflammation – Several peptides produced by proteolytic cleavage of complement proteins bind to vascular endothelial cells and lymphocytes. These cells then produce cytokines which stimulate inflammation and enhances responses to foreign antigens.
Opsonization – Certain complement proteins can bind to virions. Phagocytic cells with receptors for these complement proteins can then engulf the virus particles and destroy them. This process is called opsonization.
Solubilization of immune complexes – Some virus infections that are not cytopathic – the virus does not kill cells – lead to the accumulation of antibody-virus complexes. When these immune complexes lodge in blood vessels they can cause damage. An example is glomerulonephritis caused by deposition of antibody-antigen complexes in the kidney. Some complement proteins can disrupt these complexes and facilitate their clearance from the circulatory system.
There are three different complement pathways: classical, alternative, and mannan-binding. Unfortunately the nomenclature of the complement proteins is confusing, because they were named as they were discovered, not according to their function (see illustration below of the classical pathway). We’ll discuss the different pathways in the course of several posts. Don’t be daunted by the apparent complexity; stay with me and you’ll have a good appreciation of an extremely important part of our immune defense system.
And yes, viruses have evolved to modify the complement system.
In contrast to acute viral infections, persistent infections last for long periods, and occur when the primary infection is not cleared by the adaptive immune response. Varicella-zoster virus, measles virus, HIV-1, and human cytomegalovirus are examples of viruses that cause typical persistent infections. A chronic infection is a type of persistent infection that is eventually cleared, while latent or slow infections last the life of the host.
There is no single mechanism responsible for establishing a persistent infection; a key feature is reduction in host defenses and the ability of the virus to kill cells. Many arenaviruses, such as lymphocytic choriomeningitis virus, do not kill cells and will cause a persistent infection if the host cannot clear the virus. In some persistent viral infections there are alternate cycles of virion production and quiescence. An example is Epstein-Barr virus, the agent of infectious mononucleosis. After the initial bout of fever, sore throat, and swollen lymph glands, the virus establishes a dormant infection in which the viral genome persists in cells of the immune system. Periodically the infection is reactivated and infectious virions are shed in the absence of clinical symptoms. These reactivations lead to transmission of the infection to new hosts.
Bovine viral diarrhea virus infection is another example of how persistence is regulated by the interplay of the host immune response and viral cell killing. This virus establishes a lifelong persistent infection in most of the world’s cattle. The infected animals produce no detectable anti-viral antibody or T-cells. The virus is passed from the mother to fetus early in gestation. Infection does not stimulate the production of interferon (IFN), and therefore the adaptive immune system is not activated. Because infection does not kill cells, a persistent infection ensues.
Many infections persist because viral replication interferes with the function of cytotoxic T-lymphocytes (CTLs), immune cells that are extremely important for clearing viral infections. Infected cells are recognized when CTLs detect viral antigens on the cell surface. This recognition process requires presentation of the viral peptides by major histocompatibilty complex (MHC) class I proteins. Many viral proteins interfere with different steps of the MHC class I pathway, including the synthesis, processing, and trafficking of the protein. Even transport to the cell surface of viral peptides – produced from viral proteins by the large protein complex known as the proteasome – may be blocked.
An amazing example of such immune modulation occurs in cells infected with cytomegalovirus (CMV). This betaherpesvirus causes a common childhood infection of little consequence in healthy individuals. The infection is never cleared, and the virus persistently infects salivary and mammary glands and the kidney. When latently infected individuals are immunosuppressed by drugs or HIV infection, viral replication ensues with life-threatening consequences. CMV persists in the host because the viral genome encodes multiple proteins that interfere with MHC class I presentation of viral antigens. One viral protein blocks translocation of peptides into the lumen of the endoplasmic reticulum, while two other viral proteins cause degradation of MHC class I proteins before they reach the cell surface.
There are many more examples of how virus infections modulate the immune response, leading to persistent infection. Not surprisingly, many of the processing or regulatory steps that are targets of viral modulation were not even known until it was discovered that they were blocked by virus infection.
Peterhans, E. (2003). BVDV and innate immunity Biologicals, 31 (2), 107-112 DOI: 10.1016/S1045-1056(03)00024-1
Bornkamm, G. (2006). The infectious kiss: Newly infected B cells deliver Epstein-Barr virus to epithelial cells Proceedings of the National Academy of Sciences, 103 (19), 7201-7202 DOI: 10.1073/pnas.0602077103
WIERTZ, E. (1996). The Human Cytomegalovirus US11 Gene Product Dislocates MHC Class I Heavy Chains from the Endoplasmic Reticulum to the Cytosol Cell, 84 (5), 769-779 DOI: 10.1016/S0092-8674(00)81054-5