Impacte d'una variant siglec1-deficient en la patogènesi de la infecció per VIH-1 i MTB

• Autores: Susana Benet Garrabé
• Directores de la Tesis: Javier Martínez Picado (dir. tes.), Nuria Izquierdo Useros (codir. tes.)
• Lectura: En la Universitat Autònoma de Barcelona ( España ) en 2021
• Idioma: catalán
• Tribunal Calificador de la Tesis: Felipe García Alcaide (presid.), Julia Lorenzo Rivera (secret.), Beatriz Mothe Pujadas (voc.)
• Programa de doctorado: Programa de Doctorado en Bioquímica, Biología Molecular y Biomedicina por la Universidad Autónoma de Barcelona
• Materias:
  • Ciencias médicas
    • Medicina interna
      • Enfermedades infecciosas
• Enlaces
  • Tesis en acceso abierto en: TDX
• Resumen

  • Antigen presenting cells of the myeloid lineage have the ability to respond rapidly and effectively to infection by coordinating innate and adaptive immune responses. However, in the case of human immunodeficiency virus type 1 (HIV-1) infection, these cells might contribute to viral pathogenesis through the capture and transmission of infectious viral particles to target cells, a process known as trans-infection. This mechanism depends on Siglec-1 (CD169), a myeloid-cell surface receptor that recognizes sialylated gangliosides present on the viral membrane. To dissect the contribution of trans-infection in HIV-1 pathogenesis in vivo, we searched for SIGLEC1 null individuals and identified 85 heterozygous and 2 homozygous people with a loss-of-function variant that abrogates Siglec-1 expression. Importantly, cells from these individuals were defective for Siglec-1 activity in HIV-1 capture and transmission. Despite this phenotype, we did not observe prominent differences on HIV-1 susceptibility nor progression to acquired immunodeficiency syndrome (AIDS) in individuals harboring the SIGLEC1 null variant. Nonetheless, analysis of the effect of Siglec-1 truncation on progression to AIDS was not conclusive due to the limited cohort size, the lack of complete clinical records such as the seroconversion date, the restriction to study only off-therapy periods, and the co-infection with additional pathogens that might influence the observed phenotype in the opposite direction from what was expected.

    As a matter of fact, the latest limitation prompted us to investigate the effect of the SIGLEC1 null variant in HIV-1 co-infections and we found a significant association between this variant and extrapulmonary dissemination of Mycobacterium tuberculosis (Mtb) in two clinical cohorts comprising 6,256 individuals. When we analyzed the absence of Siglec-1 in a murine model, local spread of bacteria within the lung was apparent in Mtb-infected Siglec-1 knockout mice which, despite having similar bacterial load, developed more extensive lesions compared to wild type mice. Moreover, we demonstrated that Siglec-1 is necessary to induce antigen presentation through extracellular vesicle uptake. We postulate that lack of Siglec-1 delays the onset of protective immunity against Mtb by limiting antigen exchange via extracellular vesicles, allowing for an early local spread of mycobacteria that increases the risk for extrapulmonary dissemination. Overall, through this thesis we have explored the concept of antagonistic pleiotropy in co-infected individuals harboring the SIGLEC1 null variant, where the impaired immune control of Mtb in the absence of Siglec-1 could influence the clinical course of HIV-1 infected individuals, thus masking the expected benefits of this variant on delaying AIDS progression.