Introduction

Studies of host susceptibility to infectious agents typically employ single-pathogen infection models to minimize biological noise. Yet this reductionist strategy ignores a fundamental principle that the immune landscape is never static. Host defense capacity is shaped dynamically by age, sex, nutritional and allergic status, comorbidities, vaccination history, and crucially, concurrent infections. These factors collectively dictate disease outcomes in natural settings.

Coinfection involving two or more distinct pathogens can bidirectionally alter the host’s ability to control each infection independently. It affects the immunological status of the host through various mechanisms, including tissue damage, quantitative alterations of the immune response (ranging from hyperinflammation to immune suppression), as well as functional dysregulation of protective immune pathways, or changes in host cell metabolism (for review1). In the literature, superinfections are often described as exacerbations of one or the other pathology, but cases of protection during coinfection have also been reported. Predicting how one infection affects the other is essential for adapting patient treatment and/or identifying new therapeutic strategies.

With 10.8 million new cases each year and 1.25 million deaths (including 1.09 million among human immunodeficiency virus (HIV)-negative people), tuberculosis (TB) is the world’s leading cause of death from a single infectious agent.2 It is caused by Mycobacterium tuberculosis (Mtb), an aerosol-borne bacterium. The bacillus infects lung cells, mainly alveolar macrophages, where it modifies endocytic trafficking and metabolism to ensure its survival and proliferation (for review3). Infection-associated recruitment of immune cells leads to the formation of organized structures in the lungs, which may develop necrotic cores, known as granulomas, that can both restrict and sustain bacterial survival (for review4). Their rupture promotes bacterial dissemination and active disease (for review5). However, while granulomas are found in both active and latent TB infection (LTBI), their role in restricting bacillary growth and dissemination is considered a key contributor to the clinical state of latency. This form is clinically asymptomatic and affects an estimated 25% of the world’s population.6 As LTBI can persist for a lifetime, infected people are likely to be exposed to other infectious agents.

Here, we review recent studies on how TB modulates the host immune response during coinfection, highlighting the complexity and ongoing debate surrounding its impact on disease outcomes. In the first section, we examine how TB is a multifaceted disease with highly variable outcomes, as newly described disease states challenge the traditional binary classification of active and latent infection. This complexity is rarely considered in coinfection studies, complicating the interpretation of findings and limiting their translational relevance. This first section also introduces the key concepts of Mtb infection that frame the sections that follow. To also facilitate clarity, Table 1 summarizes the definitions of the terms used in this review concerning TB and coinfections. Following this, our initial focus is on past TB epidemics, where historical data and modeling provide insights into how ancient outbreaks shaped interactions with other pathogens. Subsequently, we turn to epidemiological data, which offer a glimpse into the global landscape of coinfections involving Mtb and their prevalence within populations. Finally, we explore translational and experimental models that connect epidemiological data with cellular mechanisms, shedding light on Mtb’s interactions with other pathogens at the immunological level. Through this analysis, we aim to enhance our understanding of host immunity in the context of coinfection with Mtb, and highlight the need for more integrative and multidisciplinary approaches to fully capture the complexity of coinfections with Mtb.

Terminology | Definition (as used in this review)
TB (disease) | (tuberculosis) clinical disease caused by Mycobacterium tuberculosis, classically identified by immunological tests (e.g., TST or IGRA). In this review, the term “TB” is used to refer to tuberculosis disease in a general sense, encompassing the full spectrum of infection from latent to active states.
Mtb | (Mycobacterium tuberculosis) the bacterial pathogen responsible for tuberculosis, encompassing genetically diverse lineages with distinct epidemiological and immunological characteristics.
Mtb infection | (Mycobacterium tuberculosis infection) the presence of Mycobacterium tuberculosis within the host, regardless of clinical manifestation. The term “Mtb infection” is the most widely used throughout this review, particularly in in vivo and in vitro studies.
Active TB | (active tuberculosis) a state of Mycobacterium tuberculosis infection in which ongoing bacterial replication leads to clinical disease, with detectable pathology and transmissibility, accompanied by symptomatic, radiological, and/or microbiological evidence. In this review, the term “active TB” is used only when explicitly employed by the original study, with the corresponding detection method indicated in Tables S1 and S2.
LTBI | (latent tuberculosis infection) a state of persistent Mycobacterium tuberculosis infection without clinical signs or symptoms of disease, in which bacterial replication is contained by the host immune response, classically identified by immunological tests (e.g., TST or IGRA). In this review, the term “LTBI” is used only when explicitly employed by the original study, with the corresponding detection method indicated in Tables S1 and S2.
Coinfection | the simultaneous or sequential presence of two or more infectious agents within the same host, irrespective of whether these infections interact biologically or clinically. In this review, the term “coinfection” is also used when the temporal sequence of infections is unknown (when it is not clear which pathogen was acquired first).
Superinfection | acquisition of a secondary infectious agent occurring after the establishment of a primary infection. In this review, the term “superinfection” emphasizes the temporal sequence and is used to refer to the secondary infection.