S100A4+ macrophages facilitate zika virus invasion and persistence in the seminiferous tubules via interferon-gamma mediation

Abstract

Testicular invasion and persistence are features of Zika virus (ZIKV), but their mechanisms are still unknown. Here, we showed that S100A4+ macrophages, a myeloid macrophage subpopulation with susceptibility to ZIKV infection, facilitated ZIKV invasion and persistence in the seminiferous tubules. In ZIKV-infected mice, S100A4+ macrophages were specifically recruited into the interstitial space of testes and differentiated into interferon-γ-expressing M1 macrophages. With interferon-γ mediation, S100A4+ macrophages down-regulated Claudin-1 expression and induced its redistribution from the cytosol to nucleus, thus increasing the permeability of the blood-testis barrier which facilitated S100A4+ macrophages invasion into the seminiferous tubules. Intraluminal S100A4+ macrophages were segregated from CD8+ T cells and consequently helped ZIKV evade cellular immunity. As a result, ZIKV continued to replicate in intraluminal S100A4+ macrophages even when the spermatogenic cells disappeared. Deficiencies in S100A4 or interferon-γ signaling both reduced ZIKV infection in the seminiferous tubules. These results demonstrated crucial roles of S100A4+ macrophages in ZIKV infection in testes.

Author summary

Zika virus (ZIKV), a flavivirus usually transmitted by mosquito bites, was recently reported to establish long-term infection in testes and consequently to transmit sexually from male to female. To uncover the underlying mechanisms, we characterized the gene expression profile of ZIKV-infected mouse testes and selected S100A4+ macrophages as crucial factors for long-term ZIKV infection in testes. S100A4+ macrophages originate from bone marrow and are susceptible to ZIKV infection. Using ZIKV susceptible mice, we found that ZIKV infection attracted S100A4+ macrophages to accumulate in the testes and differentiate into interferon-γ-expressing cells. In further experiments, we introduced S100A4+ macrophages-depleted mice and interferon-I/II signaling deficient mice. We demonstrated that interferon-γ secreted by S100A4+ macrophages induced the tight junction protein Claudin-1 to translocate from the plasma membrane into nuclei, thus increasing the permeability of the blood-testis barrier, an indispensable structure surrounding the seminiferous tubules and protecting spermatogenic cells inside from viral infection and immune attack. Taken together, we proposed a mechanism for the long-term ZIKV infection, in which S100A4+ macrophages not only function as Trojan horses to bring ZIKV into the seminiferous tubules, but also serve as a solid shelter for ZIKV replication even when spermatogenic cells have been largely destroyed by ZIKV infection.