Fiette, L. | Search bioRxiv

bioRxiv2024

Type 1 diabetes and parasite infection: an exploratory study in the NOD mouse

Microorganisms have long been suspected to influence the outcome of immune-related syndromes, particularly autoimmune diseases. Type 1 diabetes (T1D) results from the autoimmune destruction of the pancreatic islets insulin-producing beta cells, causing high glycemia levels. Genetics is part of its etiology, but environmental factors, particularly infectious microorganisms, also play a role. It was shown that bacteria, viruses, and parasites, influence the outcome of T1D in mice and humans. We have used the Non-Obese Diabetic (NOD) mouse that spontaneously develops T1D to address the influence of a parasitic infection, leishmaniasis. Leishmania amazonensis are intracellular eukaryotic parasites replicating predominantly in macrophages and are responsible for cutaneous leishmaniasis. The implication of Th1 immune responses in T1D and leishmaniasis led us to study this parasite in the NOD mouse model. We have previously constructed osteopontin knockout mice in an NOD genetic background and demonstrated that this protein plays a role in the T1D phenotype. In addition, osteopontin (OPN) has been found i) to play a role in the immune response to various infectious microorganisms and ii) to be implicated in other autoimmune conditions, such as multiple sclerosis in humans and experimental autoimmune encephalomyelitis (EAE) in mice. We present herein data demonstrating the implication of OPN in the response to Leishmania in the NOD mouse and the influence of this parasitic infection on T1D. This exploratory study aims to investigate the environmental infectious component of the autoimmune response, including through Th1 immunity, common to both T1D and leishmaniasis.

immunology↗

bioRxiv2020

Escape of TLR5 Recognition by Leptospira spp: A Rationale for Atypical Endoflagella

Leptospira interrogans are invasive bacteria responsible for leptospirosis, a worldwide zoonosis. They possess two periplasmic endoflagella that allow their motility. L. interrogans are stealth pathogens that escape the innate immune responses of the NOD-like receptors NOD1/2, and the human Toll-like receptor (TLR)4, sensing peptidoglycan and lipopolysaccharide (LPS), respectively. TLR5 is another receptor of bacterial cell wall components, recognizing flagellin subunits. To study the contribution of TLR5 in the host defense against leptospires, we infected WT and TLR5 deficient mice with pathogenic L. interrogans and tracked the infection by in vivo live imaging of bioluminescent bacteria or by q-PCR. We did not identify any protective or inflammatory role of murine TLR5 to control pathogenic Leptospira. Likewise, subsequent in vitro experiments showed that infections with different live strains of L. interrogans and L. biflexa did not trigger TLR5. However, unexpectedly, heat-killed bacteria stimulated human and bovine TLR5, although barely mouse TLR5. Abolition of TLR5 recognition required extensive boiling time of the bacteria or proteinase K treatment, showing an unusual high stability of the leptospiral flagellins. Interestingly, using antimicrobial peptides to destabilize live leptospires, we detected some TLR5 activity, suggesting that TLR5 could participate in the fight against leptospires in humans or cattle. Using different Leptospira strains with mutations in flagellin proteins, we further showed that neither FlaAs nor Fcps participated in the recognition by TLR5, suggesting a role for the FlaBs. These have structural homology to Salmonella FliC, and conserved residues important for TLR5 activation, as shown by in silico analyses. Accordingly, we found that leptospires regulate the expression of FlaB mRNA according to the growth phase in vitro, and that infection with L. interrogans in hamsters and in mice downregulated the expression of the FlaBs but not the FlaAs subunits. Altogether, in contrast to different bacteria that modify their flagellin sequences to escape TLR5 recognition, our study suggests that the peculiar central localization and stability of the FlaB monomers in the periplasmic endoflagella, associated with the downregulation of FlaB subunits in hosts, constitute an efficient strategy of leptospires to escape TLR5 recognition and the immune response.

immunology↗