The laboratory is seeking a highly motivated second year master student in Cell biology and/or Immunology to join our team, starting in January for a 6 months internship. The primary focus of our research is to understand how semen modulates mucosal immunity by examining the effects of polyamines on immune cells present in or recruited to mucosal tissues.
Polyamines in semen: modulators of mucosal immune responses during HIV-1 transmission
Viral infectious diseases, such as HIV-1, are a significant public health concern, having caused over 36 million deaths globally. Innate immune cells, including plasmacytoid dendritic cells (pDCs), play a critical role in early defense by producing antiviral interferons (IFNs) and cytokines. The immune system detects pathogens through pattern-recognition receptors (PRRs) and initiates responses via sensors like Toll-Like Receptors (TLRs). Although type I IFNs typically signal the activation of immune defenses, their prolonged activity can be harmful, contributing to conditions like AIDS and autoimmune diseases. Monoamines (such as histamine and dopamine) and polyamines (like spermine and spermidine) have been found to modulate immune responses, particularly inhibiting IFN-I production. These molecules interact with the CXCR4 receptor, which is widely expressed in immune cells, to suppress immune activation. The interaction of polyamines with CXCR4 in mucosal tissues may promote early HIV-1 transmission by dampening immune defenses, a finding that opens new therapeutic research directions.
The primary objective of the team focuses on the role of semen-derived polyamines, particularly spermine and spermidine, in shaping innate immune responses and facilitating HIV-1 transmission. Our previous findings show that these polyamines bind to the CXCR4 coreceptor and selectively inhibit X4-tropic HIV-1 strains entry, while having no effect on R5-tropic viruses. In addition, preliminary data indicate that spermine and spermidine suppress type I interferon responses in plasmacytoid dendritic cells and induce a senescence-like state. In T cells, polyamines seem to block their proliferation and to favor their acquisition of regulatory properties. All these events may weaken antiviral immunity at mucosal surfaces and creating conditions favorable for viral replication and persistence.
The proposed research project aims to describe the effects of polyamines on myeloid cells present in or recruited to mucosal tissues, particularly dendritic cells and macrophages. Monocyte-derived dendritic cells and macrophages will be generated from CD14+ blood monocytes cultured with GM-CSF/IL-4 or M-CSF, respectively, in the presence or absence of spermine or seminal plasma. The impact of polyamines on cell differentiation, polarization, and function will then be evaluated.
Overall, this project seeks to provide fundamental insights into how semen-derived polyamines alter innate immune responses at mucosal sites, potentially promoting immune evasion and enhancing HIV-1 transmission and persistence.
Relevant Publications:
Harms M*, Smith N*, et al., Spermine and spermidine bind CXCR4 and inhibit CXCR4- but not CCR5-tropic HIV-1 infection. Science Advances. 2023 July 5;9,eadf825. doi:10.1126/sciadv.adf82512023 PMID: 37406129
Smith N, et al. Control of TLR7-mediated type I IFN signaling in pDCs through CXCR4 engagement – a new target for Lupus treatment. Science Advances. 2019 Jul 10;5(7):eaav9019. DOI: 10.1126/sciadv.aav9019 PMID: 31309143
Smith N, et al., Natural amines inhibit activation of human plasmacytoid dendritic cells through CXCR4 engagement. Nature Communications. 2017 Feb 9;8:14253. DOI: 10.1038/ncomms14253 PMID: 28181493
Contacts :
Nikaïa SMITH, CRCN ATIP-Avenir, nikaia.smith@inserm.fr; Dominique CATHELIN, IR, dominique.cathelin@inserm.fr
Mucosal Viral Immune Responses (MuVIRep) Team