Elevated Inflammation Associated with Markers of Neutrophil Function and Gastrointestinal Disruption in Pilot Study of <i>Plasmodium fragile</i> Co-Infection of ART-Treated SIVmac239+ Rhesus Macaques
Sydney M. Nemphos,
Hannah C. Green,
James E. Prusak,
Sallie L. Fell,
Kelly Goff,
Megan Varnado,
Kaitlin Didier,
Natalie Guy,
Matilda J. Moström,
Coty Tatum,
Chad Massey,
Mary B. Barnes,
Lori A. Rowe,
Carolina Allers,
Robert V. Blair,
Monica E. Embers,
Nicholas J. Maness,
Preston A. Marx,
Brooke Grasperge,
Amitinder Kaur,
Kristina De Paris,
Jeffrey G. Shaffer,
Tiffany Hensley-McBain,
Berlin Londono-Renteria,
Jennifer A. Manuzak
Affiliations
Sydney M. Nemphos
Division of Immunology, Tulane National Primate Research Center, Covington, LA 70433, USA
Hannah C. Green
Division of Immunology, Tulane National Primate Research Center, Covington, LA 70433, USA
James E. Prusak
Division of Immunology, Tulane National Primate Research Center, Covington, LA 70433, USA
Sallie L. Fell
Division of Immunology, Tulane National Primate Research Center, Covington, LA 70433, USA
Kelly Goff
Division of Microbiology, Tulane National Primate Research Center, Covington, LA 70433, USA
Megan Varnado
Division of Immunology, Tulane National Primate Research Center, Covington, LA 70433, USA
Kaitlin Didier
Division of Immunology, Tulane National Primate Research Center, Covington, LA 70433, USA
Natalie Guy
Division of Immunology, Tulane National Primate Research Center, Covington, LA 70433, USA
Matilda J. Moström
Division of Immunology, Tulane National Primate Research Center, Covington, LA 70433, USA
Coty Tatum
Division of Microbiology, Tulane National Primate Research Center, Covington, LA 70433, USA
Chad Massey
Division of Immunology, Tulane National Primate Research Center, Covington, LA 70433, USA
Mary B. Barnes
Division of Microbiology, Tulane National Primate Research Center, Covington, LA 70433, USA
Lori A. Rowe
Division of Microbiology, Tulane National Primate Research Center, Covington, LA 70433, USA
Carolina Allers
Division of Immunology, Tulane National Primate Research Center, Covington, LA 70433, USA
Robert V. Blair
Division of Comparative Pathology, Tulane National Primate Research Center, Covington, LA 70433, USA
Monica E. Embers
Division of Immunology, Tulane National Primate Research Center, Covington, LA 70433, USA
Nicholas J. Maness
Division of Microbiology, Tulane National Primate Research Center, Covington, LA 70433, USA
Preston A. Marx
Division of Microbiology, Tulane National Primate Research Center, Covington, LA 70433, USA
Brooke Grasperge
Division of Veterinary Medicine, Tulane National Primate Research Center, Covington, LA 70433, USA
Amitinder Kaur
Division of Immunology, Tulane National Primate Research Center, Covington, LA 70433, USA
Kristina De Paris
Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, NC 27559, USA
Jeffrey G. Shaffer
Department of Biostatistics and Data Science, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA 70112, USA
Tiffany Hensley-McBain
McLaughlin Research Institute for Biomedical Sciences, Great Falls, MT 59405, USA
Berlin Londono-Renteria
Department of Tropical Medicine and Infectious Disease, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA 70112, USA
Jennifer A. Manuzak
Division of Immunology, Tulane National Primate Research Center, Covington, LA 70433, USA
Human immunodeficiency virus (HIV) and malaria, caused by infection with Plasmodium spp., are endemic in similar geographical locations. As a result, there is high potential for HIV/Plasmodium co-infection, which increases the pathology of both diseases. However, the immunological mechanisms underlying the exacerbated disease pathology observed in co-infected individuals are poorly understood. Moreover, there is limited data available on the impact of Plasmodium co-infection on antiretroviral (ART)-treated HIV infection. Here, we used the rhesus macaque (RM) model to conduct a pilot study to establish a model of Plasmodium fragile co-infection during ART-treated simian immunodeficiency virus (SIV) infection, and to begin to characterize the immunopathogenic effect of co-infection in the context of ART. We observed that P. fragile co-infection resulted in parasitemia and anemia, as well as persistently detectable viral loads (VLs) and decreased absolute CD4+ T-cell counts despite daily ART treatment. Notably, P. fragile co-infection was associated with increased levels of inflammatory cytokines, including monocyte chemoattractant protein 1 (MCP-1). P. fragile co-infection was also associated with increased levels of neutrophil elastase, a plasma marker of neutrophil extracellular trap (NET) formation, but significant decreases in markers of neutrophil degranulation, potentially indicating a shift in the neutrophil functionality during co-infection. Finally, we characterized the levels of plasma markers of gastrointestinal (GI) barrier permeability and microbial translocation and observed significant correlations between indicators of GI dysfunction, clinical markers of SIV and Plasmodium infection, and neutrophil frequency and function. Taken together, these pilot data verify the utility of using the RM model to examine ART-treated SIV/P. fragile co-infection, and indicate that neutrophil-driven inflammation and GI dysfunction may underlie heightened SIV/P. fragile co-infection pathogenesis.
