Difference in cellular response due to secondary bacterial messenger in Oasl1 KO mouse

Abstract

A role of interferons during bacterial or viral infection has always been a subject of much interest. Investigations led by researchers since early 1900's led to great discoveries including discovery of JAK-STAT pathway and different types of IFNs.. However, we still do not fully understand how IFNs communicate among themselves. Moreover, the role of type I IFNs during bacterial infection leaves much room for discussion.

c-di-GMP and c-di-AMP are bacterial secondary messengers that are known to initiate bio-film formation and mediate proliferation of bacteria inside cytosol. PRRs recognize these molecules and initiate anti-bacterial defense against them. Recently, a group of researchers reported that these nucleotides can induce type I IFNs production in STING dependent manner.

In this study, we used Oasl1 transgenic mice, which are known to produce increased level of type I IFNs in response to pathogenic invasion in order to delineate the significance of production of type I IFNs during bacterial infection. We sought to mimic this condition by transfecting BMDMs from Oasl1 KO mice with bacterial secondary messengers.

We discovered increased type I IFNs mRNA expression in KO mice compared to WT mice. This led to increased mRNA transcription of various cytokines in KO mice, notably IL-10 and CXCL10. On the other hand, mRNA expression of IL-1β increased in WT mice. Interestingly, TNFα that are known to be regulated by IL-10, did not differ either in mRNA level measured by qPCR analysis or protein level measured by ELISA suggesting NF-κB pathway is not altered in Oasl1 KO mice during bacterial infection. Increase in IL-10 level in KO mice may lead to inhibition of anti-bacterial peptides secreted by IFNγ induced macrophages. This indicate that increased type I IFN production may be harmful to the host during infection because bacteria cannot be suppressed properly.

Higher expression of IL-1β mRNA in WT compared to that of KO may be explained by increased IL-10 level in KO mice. Yet, protein levels and mechanism for regulation should be explored as there are two reported pathways for regulation. CXCL10 is mainly produced by IFNγ induced macrophages; thus, increase in mRNA expression in KO mice should be investigated.

Since c-di-GMP and c-di-AMP work along with other factors in bacteria, BMDMs from Oasl1 WT and KO were treated with BCG. While mRNA expression of IL-10 showed significant difference between WT and KO, protein level of cells treated with BCG did not show much difference. Further investigation regarding pathology of BCG should be conducted to better understand this phenomenon.

Our study indicates that increase in production of type I IFNs can lead to worsening of bacterial infection and patients with autoimmune disease may be more susceptible to invasion by certain types of bacteria.