Diverse infection models demonstrate robust resistance of Mycobacterium tuberculosis to innate immunity

Abstract Mycobacterium tuberculosis (Mtb) is a robust activator of innate immunity. However, there is little evidence that innate immune mechanisms control Mtb before the onset of adaptive immunity. Prior work has generally used specific pathogen-free (SPF) mouse models and relatively large infectious doses, which may obscure the capacity of innate immunity to control Mtb. Here, we performed ultra-low dose Mtb infections and found that the initial innate immune response was unable to curb even minimal Mtb infectious doses. Additionally, we primed the immune systems of C57BL/6 mice by co-housing with “pet shop” mice prior to Mtb exposure. Co-housed mice were as susceptible to Mtb infection as SPF mice. To more specifically pre-activate innate immunity at the site of Mtb infection, we also infected the lungs of mice with Legionella pneumophila (Lp) prior to Mtb. Innate immunity alone can clear large doses (>100,000 CFU) of Lp from the lung within a few days. However, pre-infection with Lp only modestly reduced Mtb CFU compared to mice infected with only Mtb, indicating that Mtb can robustly replicate even in the presence of a strong innate inflammatory response. We performed single-cell RNA-sequencing on myeloid cells from mice either infected with Mtb alone or mice primed with Lp. We found that Lp priming before Mtb infection induced measurable changes in myeloid cells responding to Mtb, but these changes had little effect on innate control of Mtb. Together, these data demonstrate the robust resistance of Mtb to innate immune clearance under diverse experimental conditions. Competing Interest Statement The authors have declared no competing interest. Footnotes This version has been reformatted for readability.