Concurrent infection with Mycobacterium tuberculosis confers robust protection against secondary infection in macaques

Abstract

For many pathogens, including most targets of effective vaccines, infection elicits an immune response that confers significant protection against reinfection. There has been significant debate as to whether natural Mycobacterium tuberculosis (Mtb) infection confers protection against reinfection. Here we experimentally assessed the protection conferred by concurrent Mtb infection in macaques, a robust experimental model of human tuberculosis (TB), using a combination of serial imaging and Mtb challenge strains differentiated by DNA identifiers. Strikingly, ongoing Mtb infection provided complete protection against establishment of secondary infection in over half of the macaques and allowed near sterilizing bacterial control for those in which a secondary infection was established. By contrast, boosted BCG vaccination reduced granuloma inflammation but had no impact on early granuloma bacterial burden. These findings are evidence of highly effective concomitant mycobacterial immunity in the lung, which may inform TB vaccine design and development.

Multimodal profiling of lung granulomas reveals cellular correlates of tuberculosis control

“…We evaluated cumulative bacterial burden (chromosomal equivalents, CEQ -derived from live + dead Mtb) to determine whether low CFU reflected reduced bacterial growth or increased bacterial killing (Cadena et al, 2018;Lin et al, 2014b;Munoz-Elias et al, 2005). We observed no significant difference in CEQ values between granulomas with low and high CFU (p>0.99, Kruskal-Wallis test with Dunn's multiple testing correction) ( Figure 1F), indicating that granulomas supported roughly similar cumulative Mtb growth over the course of infection.…”

“…Strikingly, however, individual granulomas within a single host follow independent trajectories with respect to inflammation, cellular composition, reactivation risk, and ability to kill Mtb (Coleman et al, 2014b;Gideon et al, 2015;Lenaerts et al, 2015;Lin et al, 2013;Lin et al, 2014b;Malherbe et al, 2016;Martin et al, 2017). We and others have systematically profiled cellular immune responses of individual cell types in macaque lung granulomas, including T cells (Diedrich et al, 2020;Foreman et al, 2016;Gideon et al, 2015;Lin et al, 2012;Mattila et al, 2011;Wong et al, 2018), macrophages (Mattila et al, 2013), B cells (Phuah et al, 2016;Phuah et al, 2012), and neutrophils (Gideon et al, 2019;Mattila et al, 2015), and examined the instructive roles of cytokines including IFN-γ, IL-2, TNF, IL-17 and IL-10 (Gideon et al, 2015;Lin et al, 2010;Wong et al, 2020). These analyses have enabled key insights into how specific canonical cell types and effector molecules relate to bacterial burden; for example, they revealed that balanced production of pro-and anti-inflammatory cytokines by granuloma T cells associates with bacterial control.…”

CD11cHi monocyte-derived macrophages are a major cellular compartment infected by Mycobacterium tuberculosis

“…The basis for restrictive versus permissive granulomas may be linked to how T cells recognize and inhibit intracellular bacterial growth, which could vary by the local lung microenvironment, the cell type infected, and the ability of the bacilli to evade detection [61,62]. Increasingly, AM are regarded as a protected niche occupied by Mtb, as host resistance is enhanced following AM depletion in the mouse model [13,14].…”

Contained Mycobacterium tuberculosis infection induces concomitant and heterologous protection

“…Samples were scored on a 0-4 extent scale (0 = normal; 1 = <5%; 2 = 6-30%, 3 = 31-60%, 4 = >60%) for the fraction of the lung affected in any manner (Extent 1) and for the fraction of the lung affected in the worst manner (Extent 2). Samples were scored on a 0-4 scale (0 = none; 1 = few (<5 in focus); 2 = mild numbers (5-10); 3 = moderate numbers (11)(12)(13)(14)(15)(16)(17)(18)(19)(20); 4 = marked numbers (>20)) for numbers of mixed granulomas (ill-formed granulomas with a mixture of macrophages and lymphocytes), defined granulomas (well-defined with separation of macrophages, epithelioid, or multinucleated giant cells with lymphoid aggregates), perivascular lymphoid aggregates, peribronchiolar lymphoid aggregates, histocytes (macrophages), foamy macrophages, neutrophils, cholesterol clefts, and acid-fast bacteria. Scoring was performed by a pathologist who was blinded to the experimental condition of each sample.…”

“…Both historical cohort studies and contemporary epidemiological studies demonstrate that prior infection is protective against re-infection [13,14]. In a non-human primate model, prior infection with Mtb conferred significant protection against aerosol challenge [15]. The phenomenon of a low-grade infection protecting against subsequent infections with the same pathogen has led to the development of almost all live vaccines currently in use, including those based on bacteria (BCG) or experimental vaccines against parasites (Leishmania) [16].…”