Shujie Wang,Gang Wang,Yan-Dong Tang,Siqi Li,Lei Qin,Menghang Wang,Yong-Bo Yang,Marcelo Gottschalk,Xuehui Cai

Microbiol Spectr.2022 Oct 26;e0321022.doi: 10.1128/spectrum.03210-22. Online ahead of print.

Abstract

Little is known about the damage to the important peripheral immune organ spleen caused by Streptococcus suis infection. In this study, we found that S. suis induced splenomegaly and lymphocyte disruption in spleens of mice. To explore the mechanism of splenic lesions induced by S. suis, we conducted further studies. The results showed that S. suis induced apoptosis in B cells, which is related to the cleavage of caspase-3 and caspase-8, but not the release of apoptosis-inducing factor (AIF). Thus, S. suis induced apoptosis in the spleen through caspase-dependent and AIF-independent pathways. Inflammation lesions induced in the spleen of infected mice were also investigated; we found macrophages increased in histopathological lesions of infected spleens from 12 h postinoculation to 7 days postinoculation (dpi), and the type of increased macrophages was M1 type by confocal microscopy, which can secrete proinflammatory cytokines. Meanwhile, inflammasome NLRP3 and caspase-1 were activated, and gasdermin D (GSDMD) was cleaved, which causes pyroptosis that may result in the release of numerous proinflammatory cytokines. What's more, the increase of p-JNK and p-p38 indicated that the MAPK pathway was also involved in the proinflammatory responses during S. suis infection, whereas anti-inflammatory responses in spleen were suppressed, with regulatory T cells (Tregs) upregulating at 1 dpi. Taken together, proinflammatory immune responses dominate in early infection, which induce splenomegaly and splenocyte apoptosis. This is the first report of mechanisms associated with S. suis-induced splenic lesions. IMPORTANCE Streptococcus suis serotype 2 is considered an emerging pathogen and represents a threat to humans and animals. The spleen is an important peripheral immune organ, and splenomegaly is a consequence of lesions and an important clinical indicator of S. suis infection. However, knowledge of the mechanisms underlying spleen lesions is still very limited. In the present work, we made the investigation to explain the phenomenon and the related immunomodulation in a mouse infection model. The obtained results show that inflammation contributes to splenomegaly, while apoptosis contributes to lymphocyte disruption in spleens. Related signaling pathways were discovered which have never been associated with S. suis-induced splenic injury. The new knowledge generated will help us better understand the mechanism of S. suis pathogenesis.

Keywords: Streptococcus suis; apoptosis; inflammation; pyroptosis; splenomegaly.