Chronic pneumonia despite adaptive immune response to Mycobacterium bovis BCG in MyD88-deficient mice

The Toll-like and IL-1 family receptors play critical roles in innate and adaptive immunity against intracellular pathogens. Although previous data demonstrated the importance of TLRs and IL-1R signaling events for the establishment of an effective immune response to mycobacteria, the possible function of the adaptor molecule IL-1R–associated kinase (IRAK)-4 against this pathogen has not been addressed. In this study, we determined the role of IRAK-4 in signaling pathways responsible for controlling mycobacterial infections. This kinase is important for the production of IL-12 and TNF-α by macrophages and dendritic cells exposed to mycobacteria. Moreover, Mycobacterium bovis–infected IRAK-4–knockout macrophages displayed impaired MAPK and NF-κB activation. IL-1β secretion and caspase-1 activation were also dependent on IRAK-4 signaling. Mice lacking IRAK-4 showed increased M. bovis burden in spleen, liver, and lungs and smaller liver granulomas during 60 d of infection compared with wild-type mice. Furthermore, 80% of IRAK-4−/− mice succumbed to virulent M. tuberculosis within 100 d following low-dose infection. This increased susceptibility to mycobacteria correlated with reduced IFN-γ/TNF-α recall responses by splenocytes, as well as fewer IL-12p70–producing APCs. Additionally, we observed that IRAK-4 is also important for the production of IFN-γ by CD4+ T cells from infected mice. Finally, THP-1 cells treated with an IRAK-4 inhibitor and exposed to M. bovis showed reduced TNF-α and IL-12, suggesting that the results found in mice can be extended to humans. In summary, these data demonstrate that IRAK-4 is essential for innate and adaptive immunity and necessary for efficient control of mycobacterial infections.

Section: Discussionsupporting

confidence: 62%

Lack of IL-1 Receptor–Associated Kinase-4 Leads to Defective Th1 Cell Responses and Renders Mice Susceptible to Mycobacterial Infection

Marinho

Fahel

Scanga

et al. 2016

“…Therefore, we asked whether murine homologs are important for the internalization of Mycobacterium bovis BCG. We showed previously that the absence of TLR2 plus TLR4 or of MyD88 led to a reduction in BCG-GFP internalization by one third or one half, respectively (54). Macrophages lacking SIGNR1, mannose receptor, mannose receptor plus SIGNR1, MARCO, SR-A, CD36, or SR-A plus CD36 were incubated with BCG-GFP for 2 h, and the proportion of macrophages infected with one or two mycobacteria was analyzed using confocal microscopy.…”

Section: Internalization Of Bcg Into Macrophages From Prr-deficient Micementioning

confidence: 99%

Partial Redundancy of the Pattern Recognition Receptors, Scavenger Receptors, and C-Type Lectins for the Long-Term Control of Mycobacterium tuberculosis Infection

Court

Vasseur

Vacher

et al. 2010

Self Cite

Mycobacterium tuberculosis is recognized by multiple pattern recognition receptors involved in innate immune defense, but their direct role in tuberculosis pathogenesis remains unknown. Beyond TLRs, scavenger receptors (SRs) and C-type lectins may play a crucial role in the sensing and signaling of pathogen motifs, as well as contribute to M. tuberculosis immune evasion. In this study, we addressed the relative role and potential redundancy of these receptors in the host response and resistance to M. tuberculosis infection using mice deficient for representative SR, C-type lectin receptor, or seven transmembrane receptor families. We show that a single deficiency in the class A SR, macrophage receptor with collagenous structure, CD36, mannose receptor, specific ICAM-3 grabbing nonintegrin-related, or F4/80 did not impair the host resistance to acute or chronic M. tuberculosis infection in terms of survival, control of bacterial clearance, lung inflammation, granuloma formation, and cytokine and chemokine expression. Double deficiency for the SRs class A SR types I and II plus CD36 or for the C-type lectins mannose receptor plus specific ICAM-3 grabbing nonintegrin-related had a limited effect on macrophage uptake of mycobacteria and TNF response and on the long-term control of M. tuberculosis infection. By contrast, mice deficient in the TNF, IL-1, or IFN-γ pathway were unable to control acute M. tuberculosis infection. In conclusion, we document a functional redundancy in the pattern recognition receptors, which might cooperate in a coordinated response to sustain the full immune control of M. tuberculosis infection, in sharp contrast with the nonredundant, essential role of the TNF, IL-1, or IFN-γ pathway for host resistance to M. tuberculosis.

“…Although the family of TLR is involved in the immune response of the host toward mycobacteria with several mycobacterial components interacting with different TLR (25), the very vigorous T cell responses occurring during a TB infection are TLR independent. In these experiments, TLR-disabled knockout mice were incapable of controlling a TB infection; however, the T cell responses were unaffected and comparable to that seen in wild-type mice (26,27). This suggests that, as adaptive immune responses develop even in the absence of TLR involvement, an alternative route of activation is most likely involved in the priming of the cellular immune responses.…”

Section: Discussionmentioning

confidence: 83%

Novel Generation Mycobacterial Adjuvant Based on Liposome-Encapsulated Monomycoloyl Glycerol from Mycobacterium bovis Bacillus Calmette-Guérin

Andersen

Rosenkrands

Olsen

et al. 2009

The immunostimulatory activity of lipids associated with the mycobacterial cell wall has been recognized for several decades and exploited in a large variety of different adjuvant preparations. Previously, we have shown that a mycobacterial lipid extract from Mycobacterium bovis bacillus Calmette-Guérin delivered in cationic liposomes was a particular efficient Th1-inducing adjuvant formulation effective against tuberculosis. Herein, we have dissected the adjuvant activity of the bacillus Calmette-Guérin lipid extract showing that the majority of the activity was attributable to the apolar lipids and more specifically to a single lipid, monomycoloyl glycerol (MMG), previously also shown to stimulate human dendritic cells. Delivered in cationic liposomes, MMG induced the most prominent Th1-biased immune response that provided significant protection against tuberculosis. Importantly, a simple synthetic analog of MMG, based on a 32 carbon mycolic acid, was found to give rise to comparable high Th1-biased responses with a major representation of polyfunctional CD4 T cells coexpressing IFN-γ, TNF-α, and IL-2. Furthermore, comparable activity was shown by an even simpler monoacyl glycerol analog, based on octadecanoic acid. The use of these synthetic analogs of MMG represents a promising new strategy for exploiting the immunostimulatory activity and adjuvant potential of components from the mycobacterial cell wall without the associated toxicity issues observed with complex mycobacterial preparations.