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

Chege, Duncan PhD*; Higgins, Sarah J. BSc, MSc; McDonald, Chloe R. BSc, MSc*; Shahabi, Kamnoosh BSc*; Huibner, Sanja BSc*; Kain, Taylor BSc*; Kain, Dylan BSc; Kim, Connie J. BSc, MSc*; Leung, Nelly BSc, PhD; Amin, Mohsen BSc, PhD; Geddes, Kaoru BSc, MSc, PhD; Serghides, Lena BSc, PhD; Philpott, Dana J. BSc, PhD; Kimani, Joshua MBCHB, MPH§; Gray-Owen, Scott BSc, PhD; Kain, Kevin C. MD*,†,‖; Kaul, Rupert MD, PhD*,‡,§

JAIDS Journal of Acquired Immune Deficiency Syndromes: April 15th, 2014 - Volume 65 - Issue 5 - p 517–525
doi: 10.1097/QAI.0000000000000056
Basic and Translational Science

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 α4β7 on blood CD4+ and CD8+ T cells, and these α4β7+ 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 α4β7 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.

Departments of *Medicine;

Laboratory Medicine and Pathobiology;

Immunology, University of Toronto, Toronto, Ontario, Canada;

§Department of Medical Microbiology University of Nairobi, Nairobi, Kenya; and

Sandra A. Rotman Laboratories, Sandra Rotman Centre for Global Health, Tropical Disease Unit, Toronto General Hospital, University Health Network.

Correspondence to: Duncan Chege and Rupert Kaul, Clinical Science Division, University of Toronto, Medical Sciences Building, Room #6356, Toronto, Ontario, Canada M5S 1A8 (e-mail:,

Authors S.J.H. and C.R.M. contributed equally to this work.

The authors have no conflicts of interest to disclose. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Supported in part by the Canadian Institutes of Health Research (HET-85518, R.K.; MOP-115160 and MOP-13721, K.C.K.; salary awards, D.C. and S.J.H.); the Canada Research Chair Program (K.C.K.); and the GAPPS/Gates Foundation (K.C.K.).

Received October 30, 2013

Accepted October 30, 2013

© 2014 by Lippincott Williams & Wilkins