Perturbation of Thymocyte Development Underlies the PRRS Pandemic: A Testable Hypothesis

Abstract

Porcine reproductive and respiratory syndrome virus (PRRSV) causes immune dysregulation during the Critical Window of Immunological Development. We hypothesize that thymocyte development is altered by infected thymic antigen presenting cells (TAPCs) in the fetal/neonatal thymus that interact with double-positive thymocytes causing an acute deficiency of T cells that produces “holes” in the T cell repertoire allowing for poor recognition of PRRSV and other neonatal pathogens. The deficiency may be the result of random elimination of PRRSV-specific T cells or the generation of T cells that accept PRRSV epitopes as self-antigens. Loss of helper T cells for virus neutralizing (VN) epitopes can result in the failure of selection for B cells in lymph node germinal centers capable of producing high affinity VN antibodies. Generation of cytotoxic and regulatory T cells may also be impaired. Similar to infections with LDV, LCMV, MCMV, HIV-1 and trypanosomes, the host responds to the deficiency of pathogen-specific T cells and perhaps regulatory T cells, by “last ditch” polyclonal B cell activation. In colostrum-deprived PRRSV-infected isolator piglets, this results in hypergammaglobulinemia, which we believe to be a “red herring” that detracts attention from the thymic atrophy story, but leads to our second independent hypothesis. Since hypergammaglobulinemia has not been reported in PRRSV-infected conventionally-reared piglets, we hypothesize that this is due to the down-regulatory effect of passive maternal IgG and cytokines in porcine colostrum, especially TGFβ which stimulates development of regulatory T cells (Tregs).

The pig as a model for immunology research

“…In the young pig, there is a virus with severely effects on the respiratory and reproductive system: porcine reproductive and respiratory syndrome (PRRS). This virus infects thymic antigen presenting cells in the thymus and interacts with the double position T cells resulting in a loss of T helper cells (Butler et al 2019). To my knowledge only in pigs vascularized thymic lobe transplantation has been successfully established to support thymopoiesis (La Mattina et al 2002).…”

The T-Cell Response to Type 2 Porcine Reproductive and Respiratory Syndrome Virus (PRRSV)

“…One main characteristic of PRRSV-2 is its ability to actively suppress the host immune response facilitating prolonged viremia, persistence in tissues, and the development of chronic secondary infections associated with PRDC. The following mechanisms of PRRSV-2 immune suppression were reported: The inhibition of NK cell activity and Type I Interferons production in the innate response [3]; the induction of PRRSV-2 specific CD4 + CD25 + regulatory T cells (Tregs) [4,5,6,7,8,9,10,11,12]; and the dysregulation of T-cell development in the neonatal thymus [13]. Ideally for the host, an effective T-cell response to PRRSV-2 would display the characteristics of a strong T-helper type 1 (Th1) response: Early CD4 + Th proliferation and significant production of IFN-γ; the differentiation of PRRSV-reactive Th cells into both, lymph node homing central memory (T CM ) and tissue homing effector memory (T EM ) populations [14]; and the induction of multifunctional memory T cells (T multi ).…”

Infection-Associated Thymic Atrophy

“…A recent hypothesis suggests that thymic antigen presenting cells (TAPCs) infected by PRRSV interact with DP thymocytes, which results in an acute deletion of DP thymocytes and a poor ability to recognize PRRSV and other pathogens ( 115 ).…”