Bridging scales: from population patterns to animal models and cellular mechanisms of coinfection

Given the limited epidemiological data on coinfections involving Mtb, the scarcity of patient sample investigations and mechanistic studies exploring the underlying immune processes are not surprising. On one hand, clinical samples from coinfected individuals are rare and often not collected systematically, and identifying specific markers for either infection can be challenging. On the other hand, experimental coinfection models, whether in vitro or in vivo, present significant technical difficulties, as they require careful control and compatibility of both infectious agents and their respective model systems.

Despite these challenges, several studies have investigated the immunological mechanisms and implications of TB coinfection. We have gathered in Table S4 thirty-eight publications, including in vivo, in vitro, and ex vivo experiments, as well as studies based on patient-derived samples. Importantly, the choice of infection sequence and kinetics strongly shapes the research question: one may examine how a secondary infection affects Mtb control, or conversely, whether pre-existing TB alters the host’s ability to control a subsequent infection. The order of infection is indicated in the tables whenever this information was available. However, comparing infection sequences across different pathogens remains difficult due to the heterogeneity of study designs. Not all combinations have been experimentally investigated, and when they have, methodological differences often preclude meaningful comparisons.

This section on mechanistic investigations is conceptually divided into two complementary approaches: one examines how secondary infections influence the control of TB, while the other investigates whether pre-existing Mtb infection modulates the host’s ability to respond to subsequent infections.

Coinfection-driven imbalance of TB immune control

Coinfections represent a critical but often underestimated factor influencing the trajectory of Mtb infection. By altering the balance between protective and regulatory immune responses, concurrent pathogens can drive TB pathogenesis toward exacerbation, but intriguingly, under certain circumstances, they may also confer unexpected protection. Understanding these dual outcomes is essential to unravel the complex interplay between Mtb and the host immune system, as well as to identify common immunological mechanisms underlying susceptibility or resilience. To improve clarity, the following sections are therefore organized not by the nature of the secondary pathogen, but by the type of immune response that disrupts TB control.

Innate response alteration

Parasitic coinfections provide a clear illustration of how coinfecting organisms can either impair or enhance Mtb control through modulation of innate immunity. For instance, filarial antigens disrupt antigen-presenting cell maturation and pro-inflammatory cytokine expression in response to Mtb.149 Consistently, filarial infections induce the downregulation of TLR2 and TLR9 expression and function,150 which are involved in Th1 responses.29 However, parasitic infections do not uniformly impair immunity; in some cases, they appear to enhance early control of Mtb. Hookworm-infected patients’ blood had a significantly greater ability to limit Mtb growth in vitro, which was lost following hookworm treatment; this enhanced control is accompanied by a significant negative relationship between mycobacterial growth and eosinophil counts.151 Moreover, human phagocytes had an increased ability to control Mtb during early stages of helminth exposure. Pre-exposure of monocytes or macrophages, respectively collected from human PBMCs and differentiated from PBMCs, to Ascaris lumbricoides or Schistosoma mansoni proteins increased their ability to control intracellular Mtb growth; in these settings, the effects were direct and did not involve T cells.152 Yet, helminth infections have also been shown to impair Mtb control by promoting accumulation of alternatively activated macrophages through IL-4 signaling.153 Similarly, using Plasmodium falciparum-infected erythrocytes in a co-culture model, Hawkes et al. demonstrated that superinfection with this protozoan impairs the control of Mtb replication in macrophages. The authors also showed that Plasmodium falciparum-infected mice experienced an exacerbation of TB disease caused by the disruption of granulomatous lesions and the influx of dysfunctional monocytes.154 Similar results were reported in the setting of Mtb/Plasmodium yoelii coinfection.155 These observations indicate that parasitic coinfections converge on a limited set of shared immunological mechanisms, such as modulation of cytokine signaling, cell polarization, and granuloma integrity, that can either impair or transiently enhance control of Mtb. This mechanistic diversity reinforces the need to interpret individual studies within these broader immunological themes.

Adaptive response dysfunction

Adaptive immune dysfunction underlies many of the deleterious effects of coinfection on Mtb control. HIV is a well-documented example of how coinfection disrupts Mtb control, as it profoundly depletes CD4+ T cells, which are essential for controlling Mtb. In cynomolgus macaques, reactivation of LTBI following simian immunodeficiency virus (SIV) infection correlates with early T cell loss.156 HIV-1 and SIV infections are shown to deplete lung interstitial CD4+ T cells, promoting Mtb dissemination through peripheral organs.157 Yet, Bucşan et al. showed that CD4+ T cell depletion alone is insufficient to drive reactivation, as macaques treated with CD4-depleting antibodies did not consistently develop active TB, in contrast to SIV-infected animals, suggesting that additional virus-induced factors lead to reactivation.158 Influenza A virus (IAV) illustrates how acute viral coinfections can also disrupt adaptive immune responses. Coinfection with IAV alters the overall inflammatory profile during TB, characterized by lower levels of IL-17A in the sputum, higher CCL2 levels in the blood, as well as increased frequencies of IFN-γ+IL-17+CD4+ and IFN-γ+CD8+ T cells, which are dysregulated T cell populations, both associated with poor TB control.159 Consistently, pulmonary coinfection with IAV causes an impairment of the generation of effective CD8+ and CD4+ T cell responses capable of controlling concurrent mycobacterial infection.160 Together, these changes upon HIV or IAV infection reflect the detrimental impact of a dysregulated immune environment on the control of Mtb infection. Other pathogens can similarly perturb adaptive immunity, highlighting a convergent mechanism of TB exacerbation. Among children with TB, CMV is associated with a lower frequency of CD3− CD4− CD8− lymphocytes and lower frequency of NK cells in the blood.161 Chronic Helicobacter hepaticus colonization in mice induces gut dysbiosis and systemic inflammation that leads to a marked accumulation of activated pulmonary CD4+ and CD8+ T cells following Mtb challenge, associated with excessive cytokine production, loss of immune control, and severe lung tissue damage.162 Together, these studies illustrate that coinfections can compromise TB control through dysfunction of adaptive immunity, including T cell depletion, skewed cytokine responses, and impaired effector function. By highlighting these shared mechanisms, they underscore how diverse pathogens converge on the adaptive arm of the immune system to exacerbate TB.

Interferon-mediated response

Interferons are central cytokines orchestrating immune responses against intracellular pathogens. Th1 CD4+ T cells are the main source of IFN-γ, the essential cytokine for macrophage activation and bacterial control. The course of TB during coinfection largely depends on the impact of the secondary pathogen on these key components. Protective modulation of IFN-γ responses has been observed. For instance, in humans and non-human primates, Helicobacter pylori infection is associated with protection against Mtb through enhanced IFN-γ and Th1-like responses.163 Conversely, many coinfections impair antigen-specific cellular responses; for this reason, IFN-γ-mediated immunity is not uniformly protective and strongly depends on its context and specificity. For example, among children with TB, CMV-specific IFN-γ response positively correlates with increased disease risk.161 Conversely, influenza infection suppresses Mtb-specific IFN-γ responses through type I IFN signaling, leading to impaired pulmonary recruitment of protective CD4+ Th1 cells and promoting hyperinflammation and Mtb growth.159,160,164 Helminth infections illustrate the complex duality of these effects. Hookworm infections shift the immune response from protective Th1/Th17 (IFN-γ, TNF-α, IL-17A) toward regulatory T cells and Th2 (IL-10, TGFβ, IL-4, IL-13).165,166 In patients with active TB, helminths reduce IFN-γ and dual Th1/Th17 responses, which are beneficial for Mtb control, while increasing IL-10, Th2 and regulatory T cells activities.167,168 In LTBI, filarial infection also reduces Th1 and Th17 responses through upregulation of checkpoint molecules such as CTLA-4 and PD-1169; they also induce the expansion of CD4+IL-4+ memory T cells, likely suppressing Th1 cell development via Th1/Th2 cross-regulation.170 Together, these studies demonstrate that IFN-γ responses are a central target of coinfection-driven immune modulation. However, their impact on TB outcome is highly context-dependent, as protection is determined not only by the magnitude of IFN-γ production but also by its cellular source, antigen specificity, and the broader immune environment in which it is generated.

Type I IFNs are essential antiviral mediators, promoting viral clearance, activating dendritic cells, and enhancing CD8+ T cell responses. However, in the context of bacterial or chronic viral infections, type I IFNs can paradoxically have detrimental effects. In the context of TB, type I IFN signaling has been consistently associated with exacerbated disease progression and impaired bacterial control.171 This has been demonstrated in murine coinfection models: Redford et al. showed that prior infection with IAV worsened subsequent Mtb infection through a type I IFN-dependent mechanism, leading to increased mycobacterial burden.160 Similarly, infection with lymphocytic choriomeningitis virus (LCMV), a chronic viral infection, amplifies TB severity in mice by promoting type I IFN-driven immune dysregulation, including the suppression of Mtb-specific IFN-γ production and CXCL9/10 chemokine expression.172 Human studies support this dual role of type I IFNs: CMV-induced T cell activation and type I IFN production could increase the risk of TB disease severity.173 Collectively, these studies highlight the dual nature of type I IFN signaling: while critical for antiviral defense, sustained or excessive type I IFN responses during coinfection can disrupt protective antimycobacterial immunity and contribute to TB pathogenesis.

Together, these studies illustrate that interferon-mediated pathways are a major target of coinfection-driven immune modulation. Coinfecting pathogens can either impair or enhance IFN-γ responses, and type I IFN signaling often acts as a double-edged sword, promoting antiviral immunity while potentially undermining control of Mtb. This mechanistic convergence highlights the central role of interferon signaling in determining the outcome of TB during coinfection.

Immunomodulatory shifts

During coinfections, the host immune response to Mtb is shaped by complex immunomodulatory shifts, in which both pro- and anti-inflammatory pathways may contribute to protection or disease progression depending on the context.

TNF-α plays an important role in the maintenance of LTBI and long-term control of Mtb infection.54 In an LCMV/Mtb murine coinfection model, the increased amount of TNF-α compared to Mtb infection alone initially impaired Mtb growth, but the delayed lymph node transport and the antigen-specific T cell priming ultimately allow the immunologically concealed expansion of Mtb, in the absence of effective early immunosurveillance,174 which highlights that TNF-α responses can both support protection and, if dysregulated, contribute to TB progression during coinfection, underscoring the importance of time-dependent regulation of this cytokine in controlling Mtb.

Conversely, the anti-inflammatory cytokine IL-10 is a critical immunoregulatory cytokine in Mtb infection and plays a key role in susceptibility, as it was previously described to worsen TB infection by preventing phagosome maturation and phagolysosomal fusion.175 Across multiple coinfection settings, dysregulated IL-10 responses emerge as a recurrent mechanism associated with increased susceptibility or exacerbation of TB. Several pathogens have been shown to directly or indirectly amplify IL-10-mediated immunosuppression in the context of Mtb infection. CMV produces a functional analog to human IL-10, possibly worsening TB infection by reinforcing anti-inflammatory signaling.176 In malaria/TB coinfected patients, IL-10 production is increased compared to mono-infected groups, thereby promoting an anti-inflammatory response against Mtb, whereas IL-10 levels remain significantly lower in patients with LTBI.177 Similarly, it has been shown that intestinal helminth coinfection is accompanied by an increased production of IL-10 in individuals with active pulmonary TB.167 Experimental evidence further supports a causal role for this pathway, as blocking the IL-10 receptor in IAV/Mtb coinfected mice reduces bacterial burden to levels observed in Mtb-only infections, highlighting a potential therapeutic target.164 These findings illustrate that dysregulated IL-10 signaling can undermine TB immunity, and that modulation of this pathway represents a convergent mechanism by which coinfections influence TB outcomes.

Overall, insufficient pro-inflammatory and excessive anti-inflammatory responses can compromise TB control, highlighting the importance of tightly regulated cytokine signaling during coinfection.

Concurrent infections can profoundly influence the outcome of TB, either exacerbating disease progression or conferring partial protection. These opposing effects are mediated through a variety of immune mechanisms, including modulation of cytokine environments, alteration of antigen presentation, and competition for immune resources. Both innate and adaptive responses are affected, shaping the host’s ability to contain or eliminate Mtb. These mechanisms, and their consequences on TB control, are summarized in Figure 2. Importantly, studying the impact of these coinfections on Mtb infection provides dual insights: on one hand, it helps elucidate the immunological processes underlying TB reactivation or loss of bacterial control, identifying key pathways that predispose to disease progression; on the other hand, it can reveal novel targets for therapeutic intervention, as interventions aimed at modulating cytokine imbalances, checkpoint pathways, or interferon responses could restore protective immunity or limit pathological inflammation.

Figure 2: Possible modulatory effects of coinfections on TB progressionSchematic representation of the cellular interplay during Mtb infection, with a focus on macrophage and T cell interactions that contribute to granuloma formation and containment of the bacilli. The figure also highlights how coinfecting pathogens, through modulation of cytokine production, macrophage activation, or T cell functionality, can alter the local immune environment and either impair or enhance the host’s ability to control TB progression. The upper part of the figure illustrates immune mechanisms and coinfection-induced factors associated with protection against TB (green symbols), whereas the lower part depicts mechanisms that exacerbate disease progression (red symbols). LCMV: lymphocytic choriomeningitis virus; IAV: influenza A virus; CMV: cytomegalovirus; HIV: human immunodeficiency virus. Steps 2 and 4 are intentionally repeated across the figure to illustrate processes that occur simultaneously rather than sequentially. The figure was partly created using Servier Medical Art templates, provided by Servier, which are licensed under a Creative Commons Attribution 4.0 Unported License (http://smart.servier.com).

TB-primed immunity against coinfections

While much attention has been given to how coinfections influence TB progression, less is known about how the disease itself shapes the host response to secondary infections. Understanding this directionality is particularly important, as Mtb-induced immune remodeling, particularly in the case of undiagnosed LTBI, may alter susceptibility to, or the severity of, subsequent infections. However, in vitro studies addressing this question remain scarce, largely due to the limited availability of experimental models that faithfully recapitulate LTBI.

The Mackaness effect and bacterial coinfections

This possible protection caused by Mtb is not a new concept. A 1964 study, which led to what is now known as the “Mackaness effect,” described the existence of cross-protection in mice infected with three different species of intracellular bacteria: Listeria monocytogenes, Brucella abortus and Mtb.57 Subsequent studies have also demonstrated that infection of mice with Mtb conferred protection against Listeria monocytogenes.59 Nemeth et al. showed that a contained Mtb infection induces heterologous protection in mice as it reduces the bacterial burden of Listeria monocytogenes and the number of metastases caused by the B16-F10 melanoma cell line.178 This protection was associated with an enhanced activation of alveolar macrophages and accelerated recruitment of Mtb-specific T cells to the lung parenchyma. Moreover, the protection was also enhanced upon re-exposure in macaques to Mtb through aerosol challenge.179 Together, these findings suggest that Mtb infection can induce a broad state of heterologous protection against distinct intracellular pathogens, supporting the concept that chronic Mtb infection may reprogram innate and adaptive immune responses beyond TB-specific immunity.

TB-driven resistance against respiratory viruses

In the following section, SARS-CoV-2 serves as a primary model of acute respiratory viral infection, and given the large number of studies on Mtb/SARS-CoV-2 coinfection, it provides a framework to investigate how pre-existing Mtb infection influences antiviral immunity. In this context, several experimental studies describe a beneficial effect of chronic Mtb infection on SARS-CoV-2.

Evidence from mouse models demonstrates that pre-infection with Mtb reduces SARS-CoV-2 viral load and disease severity. Hildebrand et al. showed that pre-infection with Mtb 4 to 8 weeks prior to viral infection reduced the viral load in K18-hACE2 mice, which are particularly susceptible to SARS-CoV-2.180 The protective phenotype was also observed by other research teams.181,182 The authors also showed a significant reduction in bodyweight loss and viral load, not only in K18-hACE2 mice, but also in wild-type mice infected with a murine-adapted strain of SARS-CoV-2. According to Rosas-Mejia et al., the resistance of Mtb-infected mice to SARS-CoV-2 is associated with the selective expansion of antigen-specific T cell and B cell subsets, at the expense of neutrophils, NK cells, and naive T cells.181 An effect on early viral replication was also observed, which was associated with reduced viral antigen burden and consequently a diminished magnitude of the T cell response.182 Despite notable differences in experimental models, including mouse strains, viral variants and the timing and duration of each infection, the available evidence indicates that prior Mtb infection may influence subsequent antiviral responses by reshaping the pulmonary immune environment to limit early viral replication and disease severity.

Human cohort studies support these experimental findings and suggest that LTBI is associated with a distinct immune response to SARS-CoV-2 infection. In an Indian cohort, coinfected individuals exhibit, compared to those without LTBI, heightened humoral, cytokine, and acute phase responses. LTBI is associated with modulation of antibody and cytokine responses and systemic inflammation in individuals seropositive for SARS-CoV-2 infection. The increased ability of LTBI individuals to produce both binding and neutralizing antibodies against SARS-CoV-2 suggests that LTBI has a protective role against SARS-CoV-2.183 Beyond antibody responses, alterations in interferon signaling have also been reported in patients with TB and LTBI. Reports have suggested that active TB and LTBI are associated with type I IFN production.184 Importantly, the timing of type I IFN responses appears to be critical for viral control, as a retrospective study of patients with COVID-19 found that early type I IFN treatment improves disease outcome, whereas late type I IFN administration is associated with increased mortality.185

To mechanistically investigate how Mtb infection might confer protection against SARS-CoV-2, several groups have investigated the immune crosstalk between Mtb-exposed immune cells and virus-infected targets within in vitro models. Using such an approach, Williams et al. showed that Mtb-exposed PBMCs can modulate epithelial cell responses to SARS-CoV-2 infection in vitro. In co-culture systems, SARS-CoV-2-infected cells exposed to supernatants or signals from Mtb-infected PBMCs displayed enhanced transcriptional activation, including expression of pro-inflammatory cytokines such as TNF-α, IL-1β, IL-6 and IFN-γ, as well as interferon-stimulated genes such as OAS1, OAS3, MX2 and IFIH1. Importantly, IFN-γ was identified as a key mediator in this process, as neutralization of IFN-γ significantly attenuated the protective effects observed in this system.186 In line with these findings, IFN-γ levels are elevated in the context of LTBI, indicating an enhancement and activation of the immune system.187

Collectively, human cohort data and mechanistic in vitro studies suggest that Mtb infection is associated with an immune milieu characterized by enhanced antiviral responsiveness, involving both humoral immunity and interferon signaling. While in vitro systems cannot fully recapitulate in vivo coinfection dynamics, they provide valuable insight into potential mediators. For instance, these findings suggest that IFN-γ may play a pivotal role in orchestrating the immune response against a multitude of pathogens, as illustrated by SARS-CoV-2,188 and potentially extending to other viruses such as IAV,189 in which it has been shown to inhibit viral attachment.

Taken together, evidence from animal models, human cohorts, and mechanistic in vitro studies supports the notion that chronic Mtb infection can establish an antiviral state that limits SARS-CoV-2 replication and disease severity. Although the underlying mechanisms remain incompletely understood, these findings suggest that Mtb-induced immune reprogramming may contribute to broader antiviral protection.

Influence of Mtb infection on systemic pathogens

TB is known to increase HIV-1 replication, as immune cell recruitment to sites of granulomatous inflammation may facilitate rapid virus propagation.190 Macrophages, the main target of Mtb, are permissive to HIV-1,191 and it has been shown that the anti-inflammatory macrophages present in TB microenvironments form tunneling nanotubes that allow cell-to-cell viral transfer.192 Moreover, HIV and Mtb both stimulate TNF-α production, which has been shown to enhance HIV-1 replication in macrophages.193 These synergistic effects are not observed when monocyte-derived macrophages are preincubated with inactivated Mtb, as this results in a reduction of HIV-1 replication _in vitro._194

Beyond viral infections, Mtb has also been shown to influence systemic parasitic diseases. Similarly, Page et al. showed, in C57BL/6 mice, that the increased Th1 immune response caused by Mtb infection reduced the parasitemia of Plasmodium yoelii, responsible for malaria.195 Mice coinfected with Mtb and Plasmodium berghei exhibit exacerbated chronic TB but are less susceptible to parasitic infection.196 Consistent with this, recent human data support a similar trend: higher pro-inflammatory cytokines in LTBI were found to confer immunological protection against severe malaria.177 Collectively, these studies illustrate that Mtb infection can profoundly reshape systemic immune environments beyond the lung, leading to divergent outcomes during coinfection depending on the pathogen and immunological context. These findings highlight that the impact of Mtb infection extends far beyond the pulmonary compartment and can either enhance susceptibility or confer protection against secondary pathogens, depending on the balance of immune responses elicited during coinfection.

These examples illustrate a broader pattern: the delicate immune balance required to control and maintain LTBI is often disrupted by secondary infections, which can trigger reactivation or exacerbate disease. Conversely, growing in vitro and in vivo evidence suggests that TB itself, particularly its chronic form, could provide a degree of protection against other pathogens. Yet, the underlying mechanisms behind this protective effect remain poorly understood. All the hypotheses explored in the reviewed articles are summarized in Figure 3. When combined with clinical and epidemiological observations, these findings raise important questions about the broader impact of TB on susceptibility to other infections at a global scale. Yet, such patterns remain difficult to capture due to limited data and the challenges of monitoring coinfection dynamics across diverse populations over time.

Figure 3: Possible modulatory effects of TB on secondary infections progressionIllustration of hypothetical mechanisms by which a primary Mtb infection may influence the course of subsequent infections. The figure outlines how TB-induced alterations in immune cell recruitment, activation status, or cytokine production could affect the host’s response to secondary pathogens. IAV: influenza A virus; HIV: human immunodeficiency virus. The figure was partly created using Servier Medical Art templates, provided by Servier, which are licensed under a Creative Commons Attribution 4.0 Unported License (http://smart.servier.com). Icons from BioRender. Dagan, Y. (2026) (https://BioRender.com/y4mcdyo).