Infection order outweighs the role of CD4+ T cells in tertiary flavivirus exposure
Nicole Marzan-Rivera,
Crisanta Serrano-Collazo,
Lorna Cruz,
Petraleigh Pantoja,
Alexandra Ortiz-Rosa,
Teresa Arana,
Melween I. Martinez,
Armando G. Burgos,
Chiara Roman,
Loyda B. Mendez,
Elizabeth Geerling,
Amelia K. Pinto,
James D. Brien,
Carlos A. Sariol
Affiliations
Nicole Marzan-Rivera
Department of Microbiology and Medical Zoology, University of Puerto Rico-Medical Sciences Campus, San Juan, PR 00935, USA
Crisanta Serrano-Collazo
Unit of Comparative Medicine, University of Puerto Rico-Medical Sciences Campus, San Juan, PR 00935, USA
Lorna Cruz
Department of Microbiology and Medical Zoology, University of Puerto Rico-Medical Sciences Campus, San Juan, PR 00935, USA; Unit of Comparative Medicine, University of Puerto Rico-Medical Sciences Campus, San Juan, PR 00935, USA
Petraleigh Pantoja
Unit of Comparative Medicine, University of Puerto Rico-Medical Sciences Campus, San Juan, PR 00935, USA
Alexandra Ortiz-Rosa
Department of Biology, University of Puerto Rico Rio Piedras Campus, San Juan, PR 00931, USA
Teresa Arana
Department of Microbiology and Medical Zoology, University of Puerto Rico-Medical Sciences Campus, San Juan, PR 00935, USA; Unit of Comparative Medicine, University of Puerto Rico-Medical Sciences Campus, San Juan, PR 00935, USA
Melween I. Martinez
Unit of Comparative Medicine, University of Puerto Rico-Medical Sciences Campus, San Juan, PR 00935, USA; Caribbean Primate Research Center, School of Medicine, University of Puerto Rico-Medical Sciences Campus, Toa Baja, PR 00952, USA
Armando G. Burgos
Unit of Comparative Medicine, University of Puerto Rico-Medical Sciences Campus, San Juan, PR 00935, USA; Caribbean Primate Research Center, School of Medicine, University of Puerto Rico-Medical Sciences Campus, Toa Baja, PR 00952, USA
Chiara Roman
Unit of Comparative Medicine, University of Puerto Rico-Medical Sciences Campus, San Juan, PR 00935, USA
Loyda B. Mendez
Department of Science & Technology, Universidad Ana G. Mendez, Recinto de Carolina, Carolina, PR 00985, USA
Elizabeth Geerling
Department of Molecular Microbiology and Immunology, Saint Louis University, St Louis, MO 631204, USA
Amelia K. Pinto
Department of Molecular Microbiology and Immunology, Saint Louis University, St Louis, MO 631204, USA
James D. Brien
Department of Molecular Microbiology and Immunology, Saint Louis University, St Louis, MO 631204, USA
Carlos A. Sariol
Department of Microbiology and Medical Zoology, University of Puerto Rico-Medical Sciences Campus, San Juan, PR 00935, USA; Unit of Comparative Medicine, University of Puerto Rico-Medical Sciences Campus, San Juan, PR 00935, USA; Department of Biology, University of Puerto Rico Rio Piedras Campus, San Juan, PR 00931, USA; Department of Internal Medicine, University of Puerto Rico-Medical Sciences Campus, San Juan, PR 00935, USA; Corresponding author
Summary: The link between CD4+ T and B cells during immune responses to DENV and ZIKV and their roles in cross-protection during heterologous infection is an active area of research. Here we used CD4+ lymphocyte depletions to dissect the impact of cellular immunity on humoral responses during a tertiary flavivirus infection in macaques. We show that CD4+ depletion in DENV/ZIKV-primed animals followed by DENV resulted in dysregulated adaptive immune responses. We show a delay in DENV-specific IgM/IgG antibody titers and binding and neutralization in the DENV/ZIKV-primed CD4-depleted animals but not in ZIKV/DENV-primed CD4-depleted animals. This study confirms the critical role of CD4+ cells in priming an early effective humoral response during sequential flavivirus infections. Our work here suggests that the order of flavivirus exposure affects the outcome of a tertiary infection. Our findings have implications for understanding the complex flavivirus immune responses and for the development of effective flavivirus vaccines.
