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A gut reaction: The role of IL-22 and the mucosal barrier in control of HIV, hepatitis, and flu

March 21, 2011
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ResearchBlogging.org

Simply put, AIDS occurs when T cell numbers in an HIV-infected individual drop to the point where they can no longer ward off infection. The way in which HIV causes this drop in T cell number is likely not simple. Initially, the drop in T cell number during HIV infection was thought to be caused solely by lysis of T cells as the virus burst out. Although this does happen, additional mechanisms have been proposed. More recently, it was proposed that memory T cell pools are exhausted in HIV patients due to chronic immune activation. Immune activation is now considered to be the strongest predictor of disease progression in HIV-infected individuals (1). Interestingly, this chronic activation of the immune system does not appear to be in response to the AIDS virus itself, but more a result of damage to the gut caused by the virus early in infection (2).

The human gut is lined with CD4+ cells. Soon after HIV infection, the CD4+ cells of the gut are rapidly depleted. This leads to a breach in the mucosal barrier, allowing intestinal bacteria to leak out. It is this microbial translocation, or passage of bacteria through the mucosa and into the circulation and other tissues, that appears to cause much of the immune activation in HIV patients (2, 3). Evidence from SIV-infection of nonhuman primates suggests that breakdown vs. maintenance of the mucosal barrier could determine the pathogenicity of SIV, as SIV is pathogenic in rhesus macaques, whose mucosal barrier is affected, but is not pathogenic in sooty mangabeys and African green monkeys, whose mucosal barrier remains intact (2).

Given how important the mucosal barrier appears to be, it is not surprising that immunologists are working hard to determine how it helps control infection. Within the past month, I have heard two invited seminars at UGA on the subject, both focused on the role of IL-22 in maintaining the mucosal barrier. The first seminar, entitled “Mechanisms of Immuno-Regulation at Barrier Surfaces”, was given by Dr. David Artis of the University of Pennsylvania. Dr. Artis studies the role of IL-22 in maintenance of the mucosal barrier in Citrobacter rodentium-infected mice. Citrobacter rodentium infection in mice is similar to enterohemorrhagic E. Coli infection in humans, and elicits a host-protective IL-23/IL-22 pathway. Using this model, the Artis group discovered the importance of IL-22-producing CD4+ lymphoid tissue inducer-like (LTi-like) cells in maintaining the mucosal barrier (4). LTi-like cells are innate lymphoid cells that populate the mucosa-associated lymphoid tissues of adult humans and mice. When these cells are specifically depleted, bacterial break-through is observed (4). Now these cells are considered possibly more important than Th17 cells – the cells originally considered to be the main secretor of IL-22 – in IL-22 production. This may prove to be important early in HIV infection, where a loss of CD4+ cells results in microbial translocation/ bacterial breakthrough. It has yet to be determined which CD4+ cells are specifically depleted during HIV infection, and if LTi-like cells are among these. However, Artis is collaborating with Jason Brenchley to determine if LTi-like cells are depleted during HIV infection, and what the significance of this is.

The second talk I heard on IL-22 was given by Dr. Lauren Zenewicz of Yale, and focused on the role of natural killer cells in IL-22 production. Her research shows that although LTi-like cells appear to produce the most IL-22 per cell, they are a rare population in the gut. There are ~10 times more NK cells present; and although they secrete less IL-22 compared to LTi-like cells, they could be a significant source of IL-22 in the gut due to their relative abundance.

Moving away from the gut, IL-22 may also play a role in control of viral infections that affect the liver and the lungs. Although not the focal point of her talk, Dr. Zenewicz’s data on IL-22 production in the liver during ConA-mediated hepatitis shows that IL-22 can protect against tissue damage during liver inflammation (5). As liver inflammation is caused by hepatitis B and C viruses, IL-22 may be involved in control of liver damage in individuals infected with these viruses. Even so, Dr. Zenewicz believes that using this cytokine as an immune therapy could be tricky due to its contradictory pro- and anti-inflammatory functions, and that further research into its effects in different environments is required.

Having heard these two talks so closely together, I started to wonder if there were any other studies linking a breach in the mucosal barrier to disease outcome during viral infection. Upon searching PubMed, I found an Influenza study in the Journal of Immunology showing that viral inhibition of IL-17+IL-22-mediated host defenses can lead to bacterial pneumonia – a common secondary infection associated with influenza A. During coinfection of mice with influenza A and Staphylococcus aureus, S. aureus-induced IL-17, IL-22, and IL-23 decreased as a result of type I IFN production in influenza A-infected mice (6). Overexpression of IL-23 in these coinfected mice rescued IL-17 and IL-22 production, resulting in increased bacterial clearance (6). These findings show that IL-22 and IL-17 production are important in preventing secondary bacterial infections like pneumonia during influenza infection, and may be relevant to Pseudomonas aeruginosa pneumonia during HIV infection as well.

From the studies mentioned above, the role of the mucosal barrier in control of viral infection appears more indirect, with IL-22 controlling damage caused by the immune response during viral infection and preventing secondary infection. However, secondary infection can lead to death in immunosuppressed patients, like AIDS patients, making these studies particularly relevant to development of immunotherapeutic drugs for the HIV-infected.

Citations:

(1)Giorgi, J., Hultin, L., McKeating, J., Johnson, T., Owens, B., Jacobson, L., Shih, R., Lewis, J., Wiley, D., Phair, J., Wolinsky, S., & Detels, R. (1999). Shorter Survival in Advanced Human Immunodeficiency Virus Type 1 Infection Is More Closely Associated with T Lymphocyte Activation than with Plasma Virus Burden or Virus Chemokine Coreceptor Usage The Journal of Infectious Diseases, 179 (4), 859-870 DOI: 10.1086/314660

(2)Brenchley, J., & Douek, D. (2008). The mucosal barrier and immune activation in HIV pathogenesis Current Opinion in HIV and AIDS, 3 (3), 356-361 DOI: 10.1097/COH.0b013e3282f9ae9c

(3)Brenchley, J., Price, D., Schacker, T., Asher, T., Silvestri, G., Rao, S., Kazzaz, Z., Bornstein, E., Lambotte, O., Altmann, D., Blazar, B., Rodriguez, B., Teixeira-Johnson, L., Landay, A., Martin, J., Hecht, F., Picker, L., Lederman, M., Deeks, S., & Douek, D. (2006). Microbial translocation is a cause of systemic immune activation in chronic HIV infection Nature Medicine, 12 (12), 1365-1371 DOI: 10.1038/nm1511

(4)Sonnenberg GF, Monticelli LA, Elloso MM, Fouser LA, & Artis D (2011). CD4(+) lymphoid tissue-inducer cells promote innate immunity in the gut. Immunity, 34 (1), 122-34 PMID: 21194981

(5)Zenewicz LA, Yancopoulos GD, Valenzuela DM, Murphy AJ, Karow M, & Flavell RA (2007). Interleukin-22 but not interleukin-17 provides protection to hepatocytes during acute liver inflammation. Immunity, 27 (4), 647-59 PMID: 17919941

(6)Kudva A, Scheller EV, Robinson KM, Crowe CR, Choi SM, Slight SR, Khader SA, Dubin PJ, Enelow RI, Kolls JK, & Alcorn JF (2011). Influenza A inhibits Th17-mediated host defense against bacterial pneumonia in mice. Journal of immunology (Baltimore, Md. : 1950), 186 (3), 1666-74 PMID: 21178015

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