
ツベルクロシス菌複合体の遺伝的多様性は、細胞内増殖率、マクロファージ細胞死、肉芽腫形成、T細胞活性化、および特定の炎症性因子の分泌など、宿主免疫応答の様々な側面に影響を及ぼす。


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The members of the Mycobacterium tuberculosis complex (MTBC) causing human tuberculosis comprise ten phylogenetic lineages that differ in their geographical distribution. The human consequences of this phylogenetic diversity remain poorly understood. Here, we assessed the phenotypic properties at the host-pathogen interface of 14 clinical strains representing five major MTBC lineages. Using a human in vitro granuloma model combined with bacterial load assessment, microscopy, flow cytometry, and multiplexed-bead arrays, we observed considerable intra-lineage diversity. Yet, modern lineages were overall associated with increased growth rate and more pronounced granulomatous responses. MTBC lineages exhibited distinct propensities to accumulate triglyceride lipid droplets —a phenotype associated with dormancy— that was particularly pronounced in lineage 2 and reduced in lineage 3 strains. The most favorable granuloma responses were associated with strong CD4 and CD8 T cell activation as well as inflammatory responses mediated by CXCL9, granzyme B and TNF-α. Both of which showed consistent negative correlation with bacterial proliferation across genetically distant MTBC strains of different lineages. Taken together, our data indicate that different virulence strategies and protective immune traits associate with MTBC genetic diversity at lineage and strain level.

### Competing Interest Statement

The authors have declared no competing interest.

CXCL9, granzyme B and TNF-α orchestrate protective in vitro granulomatous responses across Mycobacterium tuberculosis complex lineages

ヒトツベルクロシス菌複合体の遺伝的多様性が宿主免疫応答に及ぼす影響

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生きた腐生性レプトスピラへの曝露は、病原性レプトスピラ感染症の重症化を防ぎ、宿主の生存率を高める。


Previous studies demonstrated that Leptospira biflexa , a saprophytic species, triggers innate immune responses in the host during early infection. This raised the question of whether these responses could suppress a subsequent challenge with pathogenic Leptospira . We inoculated male C3H/HeJ mice with a single or a double dose of L. biflexa before challenge with a pathogenic serovar, L. interrogans ser. Copenhageni FioCruz (LIC). Pre-challenge exposure to L. biflexa did not prevent LIC dissemination and colonization of the kidney. However, it rescued weight loss and mouse survival thereby mitigating disease severity. Unexpectedly, there was correlation between rescue of overall health (weight gain, higher survival, lower kidney fibrosis) and higher shedding of LIC in urine. This stood in stark contrast to the L. biflexa unexposed LIC challenged control. Immune responses were dominated by increased frequency of B cells and effector T helper (CD4+) cells in spleen, as well as significant increases in serologic IgG2a. Our findings suggest that exposure to live saprophytic Leptospira primes the host to develop Th1 biased immune responses that prevent severe disease induced by a subsequent challenge with a pathogenic species. Thus, hosts exposed to live saprophytic Leptospira before challenge with a pathogenic serovar may withstand LIC infection with far better outcomes. Furthermore, a status of homeostasis may have been reached after kidney colonization that helps LIC complete its enzootic cycle.

Significance Previous evidence of host innate immunity induced by live saprophytic Leptospira led us to posit that these responses might mitigate leptospirosis severity upon a subsequent challenge with a pathogenic serovar. In this study, we validated our hypothesis. This is important for development of novel strategies to control leptospirosis and for understanding the epidemiologic risk factors of this and other infectious diseases transmitted by direct contact between pathogen and host. Unexpectedly, these studies also show that there is a correlation between kidney health after L. interrogans infection (less fibrosis) and higher shedding of this spirochete in urine. This suggests that a status of homeostasis may be reached after kidney colonization by L. interrogans that helps the spirochete fulfill its enzootic cycle.

### Competing Interest Statement

The authors have declared no competing interest.

Exposure to live saprophytic Leptospira before challenge with a pathogenic serovar prevents severe leptospirosis and promotes kidney homeostasis

病原性レプトスピラ感染症を予防し-腎臓の恒常性を促進する-生きた腐生性レプトスピラへの曝露


病原性レプトスピラ感染症を予防し、腎臓の恒常性を促進する、生きた腐生性レプトスピラへの曝露
