Preclinical identification of vaccine induced protective correlates in human leukocyte antigen expressing transgenic mice infected with Coccidioides posadasii.
There is an emerging interest to develop human vaccines against medically-important fungal pathogens and a need for a preclinical animal model to assess vaccine efficacies and protective correlates. HLA-DR4 (DRB1∗0401 allele) transgenic mice express a human major histocompatibility complex class II (MHC II) receptor in such a way that CD4+T-cell response is solely restricted by this human molecule. In this study HLA-DR4 transgenic mice were immunized with a live-attenuated vaccine (ΔT) and challenged by the intranasal route with 50-70 Coccidioides posadasii spores, a potentially lethal dose. The same vaccination regimen offers 100% survival for C57BL/6 mice. Conversely, ΔT-vaccinated HLA-DR4 mice displayed 3 distinct manifestations of Coccidioides infection including 40% fatal acute (FAD), 30% disseminated (DD) and 30% pulmonary disease (PD). The latter 2 groups of mice had reduced loss of body weight and survived to at least 50days postchallenge (dpc). These results suggest that ΔT vaccinated HLA-DR4 mice activated heterogeneous immunity against pulmonary Coccidioides infection. Vaccinated HLA-DR4 mice displayed early expansion of Th1 and Th17 cells and recruitment of inflammatory innate cells into Coccidioides-infected lungs during the first 9dpc. While contraction rates of Th cells and the inflammatory response during 14-35dpc significantly differed among the 3 groups of vaccinated HLA-DR4 mice. The FAD group displayed a sharply reduced Th1 and Th17 response, while overwhelmingly recruiting neutrophils into lungs during 9-14days. The FAD group approached moribund by 14dpc. In contrast, vaccinated HLA-DR4 survivors gradually contracted Th cells and inflammatory response with the greatest rate in the PD group. While vaccinated HLA-DR4 mice are susceptible to Coccidioides infection, they are useful for evaluation of vaccine efficacy and identification of immunological correlates against this mycosis.
Department of Biology and South Texas Center for Emerging Infectious Diseases, University of Texas, San Antonio, TX, USA; Department of Microbiology and Immunology, University of Texas Health Science Center at San Antonio, TX, USA.
Brady J
BJ
Hurtgen
Department of Biology and South Texas Center for Emerging Infectious Diseases, University of Texas, San Antonio, TX, USA.
Natalia
N
Castro-Lopez
Department of Biology and South Texas Center for Emerging Infectious Diseases, University of Texas, San Antonio, TX, USA; Grupo de Micología Médica, Department of Microbiology and Parasitology, School of Medicine, Universidad de Antioquia, Medellín, Colombia.
Maria Del Pilar
MDP
Jiménez-Alzate
Department of Biology and South Texas Center for Emerging Infectious Diseases, University of Texas, San Antonio, TX, USA; Department of Microbiology and Immunology, University of Texas Health Science Center at San Antonio, TX, USA.
Garry T
GT
Cole
Department of Biology and South Texas Center for Emerging Infectious Diseases, University of Texas, San Antonio, TX, USA; Immune Defense Core, University of Texas, San Antonio, TX, USA. Electronic address: Chiungyu.Hung@UTSA.edu.
Chiung-Yu
CY
Hung
D056704:Adaptive Immunity; D000818:Animals; D003045:Coccidioides / Q000276:immunology / Q000302:isolation & purification*; D003047:Coccidioidomycosis / Q000276:immunology* / Q000382:microbiology / Q000517:prevention & control*; D016207:Cytokines / Q000096:biosynthesis; D005657:Fungal Vaccines / Q000008:administration & dosage / Q000276:immunology*; D015804:HLA-DR4 Antigen / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate; D008168:Lung / Q000276:immunology / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D013172:Spores, Fungal; D058504:Th17 Cells / Q000276:immunology; D014613:Vaccines, Attenuated
D016207:Cytokines; D005657:Fungal Vaccines; D015804:HLA-DR4 Antigen; D014613:Vaccines, Attenuated
Coccidioides; Coccidioidomycosis; Fungal vaccine; HLA-DR4 transgenic mice; Innate and adaptive immunity