Murine Plasmodium chabaudi Malaria Increases Mucosal Immune Activation and the Expression of Putative HIV Susceptibility Markers in the Gut and Genital Mucosae

Objective:To evaluate if systemic murine malarial infection enhances HIV susceptibility through parasite-induced mucosal immune alterations at sites of HIV sexual exposure. Background:Malaria and HIV have a high degree of geographical overlap and interact substantially within coinfected individuals. We used a murine model to test the hypothesis that malaria might also enhance HIV susceptibility at mucosal sites of HIV sexual exposure. Methods:Female C57/BL6 mice were infected with Plasmodium chabaudi malaria using a standardized protocol. Blood, gastrointestinal tissues, upper and lower genital tract tissues, and iliac lymph nodes were sampled 10 days postinfection, and the expression of putative HIV susceptibility and immune activation markers on T cells was assessed by flow cytometry. Results:P. chabaudi malaria increased expression of mucosal homing integrin &agr;4&bgr;7 on blood CD4+ and CD8+ T cells, and these &agr;4&bgr;7+ T cells had significantly increased co-expression of both CCR5 and CD38. In addition, malaria increased expression of the HIV co-receptor CCR5 on CD4+ T cells from the genital tract and gut mucosa as well as mucosal T-cell expression of the immune activation markers CD38, Major Histocompatibility Complex -II (MHC-II) and CD69. Conclusions:Systemic murine malarial infection induced substantial upregulation of the mucosal homing integrin &agr;4&bgr;7 in blood as well as gut and genital mucosal T-cell immune activation and HIV co-receptor expression. Human studies are required to confirm these murine findings and to examine whether malarial infection enhances the sexual acquisition of HIV.

[1]  M. Altfeld,et al.  Innate immune activation enhances hiv acquisition in women, diminishing the effectiveness of tenofovir microbicide gel. , 2012, The Journal of infectious diseases.

[2]  R. Kaul,et al.  Blunted IL17/IL22 and Pro-Inflammatory Cytokine Responses in the Genital Tract and Blood of HIV-Exposed, Seronegative Female Sex Workers in Kenya , 2012, PloS one.

[3]  M. Tremblay,et al.  Mechanisms of interaction between protozoan parasites and HIV , 2012, Current opinion in HIV and AIDS.

[4]  C. Wachihi,et al.  A distinct cytokine and chemokine profile at the genital mucosa is associated with HIV-1 protection among HIV-exposed seronegative commercial sex workers , 2012, Mucosal Immunology.

[5]  Nancy Fullman,et al.  Global malaria mortality between 1980 and 2010: a systematic analysis , 2012, The Lancet.

[6]  R. Kaul,et al.  Characterization of a Human Cervical CD4+ T Cell Subset Coexpressing Multiple Markers of HIV Susceptibility , 2011, The Journal of Immunology.

[7]  M. Wahlgren,et al.  Effect of Acute Plasmodium falciparum Malaria on Reactivation and Shedding of the Eight Human Herpes Viruses , 2011, PloS one.

[8]  P. Crowley,et al.  HIV-malaria co-infection: effects of malaria on the prevalence of HIV in East sub-Saharan Africa. , 2011, International journal of epidemiology.

[9]  R. Kaul,et al.  Identification of an innate T helper type 17 response to intestinal bacterial pathogens , 2011, Nature Medicine.

[10]  J. Mullins,et al.  Genital HIV-1 RNA Predicts Risk of Heterosexual HIV-1 Transmission , 2011, Science Translational Medicine.

[11]  R. Kaul,et al.  Biological Factors that May Contribute to Regional and Racial Disparities in HIV Prevalence , 2011, American journal of reproductive immunology.

[12]  C. Wachihi,et al.  HIV‐exposed seronegative commercial sex workers show a quiescent phenotype in the CD4+ T cell compartment and reduced expression of HIV‐dependent host factors. , 2010, The Journal of infectious diseases.

[13]  Sa Azin,et al.  An overview on the 2008 UNAIDS Report on the 2008 UNAIDS Report on the Global AIDS Epidemic. , 2010 .

[14]  Joelle M. Brown,et al.  Increased levels of immune activation in the genital tract of healthy young women from sub-Saharan Africa , 2010, AIDS.

[15]  Anand P. Patil,et al.  Estimating the Global Clinical Burden of Plasmodium falciparum Malaria in 2007 , 2010, PLoS medicine.

[16]  R. Webby,et al.  Dynamic T cell migration program provides resident memory within intestinal epithelium , 2010, The Journal of experimental medicine.

[17]  K. Ley,et al.  Role of beta7 integrins in intestinal lymphocyte homing and retention. , 2009, Current molecular medicine.

[18]  J. H. van de Wijgert,et al.  HIV incidence in sub-Saharan Africa: a review of available data with implications for surveillance and prevention planning. , 2009, AIDS reviews.

[19]  A. Wald,et al.  Persistence of HIV-1 Receptor-Positive Cells after HSV-2 Reactivation: A Potential Mechanism for Increased HIV-1 Acquisition , 2009, Nature Medicine.

[20]  W. Fawzi,et al.  Placental malaria and mother-to-child transmission of human immunodeficiency virus-1. , 2009, The American journal of tropical medicine and hygiene.

[21]  Marie-Claude Boily,et al.  Heterosexual risk of HIV-1 infection per sexual act: systematic review and meta-analysis of observational studies. , 2009, The Lancet. Infectious diseases.

[22]  Kevin Marsh,et al.  Immunity to malaria: more questions than answers , 2008, Nature Immunology.

[23]  J. Kublin,et al.  Dual Infection with HIV and Malaria Fuels the Spread of Both Diseases in Sub-Saharan Africa , 2006, Science.

[24]  M. Mack,et al.  Gut-associated lymphoid tissue-primed CD4+ T cells display CCR9-dependent and -independent homing to the small intestine. , 2006, Blood.

[25]  H. Schuitemaker,et al.  Low-Level CD4+ T Cell Activation Is Associated with Low Susceptibility to HIV-1 Infection1 , 2005, The Journal of Immunology.

[26]  Brian G. Williams,et al.  Malaria Attributable to the HIV-1 Epidemic, Sub-Saharan Africa , 2005, Emerging infectious diseases.

[27]  J. Kublin,et al.  Effect of Plasmodium falciparum malaria on concentration of HIV-1-RNA in the blood of adults in rural Malawi: a prospective cohort study , 2005, The Lancet.

[28]  P. Kaleebu,et al.  Activation by malaria antigens renders mononuclear cells susceptible to HIV infection and re‐activates replication of endogenous HIV in cells from HIV‐infected adults , 2004, Parasite immunology.

[29]  Qingsheng Li,et al.  Roles of substrate availability and infection of resting and activated CD4+ T cells in transmission and acute simian immunodeficiency virus infection. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[30]  M. Kolczak,et al.  Maternal Malaria and Perinatal HIV Transmission, Western Kenya, , 2004, Emerging infectious diseases.

[31]  E. Riley,et al.  Innate immunity to malaria , 2004, Nature Reviews Immunology.

[32]  N. Sewankambo,et al.  The effects of placental malaria on mother-to-child HIV transmission in Rakai, Uganda , 2003, AIDS.

[33]  A. Ashkar,et al.  Progesterone Increases Susceptibility and Decreases Immune Responses to Genital Herpes Infection , 2003, Journal of Virology.

[34]  M. Moriuchi,et al.  Dichotomous effects of Plasmodium falciparum antigens on expression of human immunodeficiency virus (HIV) coreceptors and on infectability of CD4 cells by HIV. , 2002, Journal of Infectious Diseases.

[35]  S. Rowland-Jones,et al.  Interactions between malaria and HIV infection-an emerging public health problem? , 2002, Microbes and infection.

[36]  M. Molyneux,et al.  Immune activation and induction of HIV-1 replication within CD14 macrophages during acute Plasmodium falciparum malaria coinfection , 2002, AIDS.

[37]  N. French,et al.  Increasing rates of malarial fever with deteriorating immune status in HIV-1-infected Ugandan adults , 2001, AIDS.

[38]  S. Meshnick,et al.  Malaria enhances expression of CC chemokine receptor 5 on placental macrophages. , 2001, The Journal of infectious diseases.

[39]  M. Quigley,et al.  Effect of HIV-1 and increasing immunosuppression on malaria parasitaemia and clinical episodes in adults in rural Uganda: a cohort study , 2000, The Lancet.

[40]  T. Quinn,et al.  Viral load and heterosexual transmission of human immunodeficiency virus type 1. Rakai Project Study Group. , 2000, The New England journal of medicine.

[41]  R. Lal,et al.  Plasmodium falciparum antigen-induced human immunodeficiency virus type 1 replication is mediated through induction of tumor necrosis factor-alpha. , 1998, The Journal of infectious diseases.

[42]  P. Kilshaw,et al.  Expression and regulation of β7(βp) integrins on mouse lymphocytes: Relevance to the mucosal immune system , 1991 .

[43]  J. Podoba,et al.  CD4+ and CD8+ T lymphocytes both contribute to acquired immunity to blood-stage Plasmodium chabaudi AS , 1991, Infection and immunity.

[44]  Anand P. Patil,et al.  The risks of malariainfection in Kenya in 2009 , 2009, BMC infectious diseases.

[45]  P. Kilshaw,et al.  Expression and regulation of beta 7(beta p) integrins on mouse lymphocytes: relevance to the mucosal immune system. , 1991, European journal of immunology.