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Mucosal Delivery of ESX-1–Expressing BCG Strains Provides Superior Immunity Against Tuberculosis in Murine Type 2 Diabetes

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Mucosal Delivery of ESX-1–Expressing BCG Strains Provides Superior Immunity Against Tuberculosis in Murine Type 2 Diabetes Mucosal delivery of ESX-1–expressing BCG strains provides superior immunity against tuberculosis in murine type 2 diabetes Harindra D. Sathkumaraa, Visai Muruganandaha,b, Martha M. Coopera,c, Matt A. Fielda,c, Md Abdul Alima,d, Roland Brosche, Natkunam Ketheesanf, Brenda Govana,g, Catherine M. Rusha,g, Lars Henningg, and Andreas Kupza,1 aCentre for Molecular Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns & Townsville, QLD 4878, Australia; bCollege of Medicine and Dentistry, James Cook University, Cairns & Townsville, QLD 4878, Australia; cCentre for Tropical Bioinformatics and Molecular Biology, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, QLD 4878, Australia; dFaculty of Veterinary Medicine, Chattogram Veterinary and Animal Sciences University, Chattogram 4225, Bangladesh; eInstitut Pasteur, Unit for Integrated Mycobacterial Pathogenomics, CNRS UMR 3525, 75015 Paris, France; fScience and Technology, University of New England, Armidale, NSW 2351, Australia; and gCollege of Public Health, Medical and Veterinary Sciences, James Cook University, Townsville, QLD 4811, Australia Edited by William R. Jacobs Jr, Albert Einstein College of Medicine, Bronx, NY, and approved July 14, 2020 (received for review February 26, 2020) Tuberculosis (TB) claims 1.5 million lives per year. This situation is (6) and delayed adaptive immune priming (7) relative to stan- largely due to the low efficacy of the only licensed TB vaccine, dard models. However, the majority of these animal models lack Bacillus Calmette–Guérin (BCG) against pulmonary TB. The meta- many features of T2D. We have recently described a robust diet- bolic disease type 2 diabetes (T2D) is a risk factor for TB and the induced animal model for T2D encompassing the cardinal features mechanisms underlying increased TB susceptibility in T2D are not of human T2D such as obesity, glucose intolerance, chronic in- well understood. Furthermore, it is unknown if new TB vaccines will flammation, hyperinsulinemia, progressive insulin resistance, and provide protection in the context of T2D. Here we used a diet-induced adipocyte and glomerular hypertrophy (8). Using this model, we murine model of T2D to investigate the underlying mechanisms of demonstrated increased bacterial burden, lung immunopathology, TB/T2D comorbidity and to evaluate the protective capacity of two and greater mortality following infections with Mycobacterium experimental TB vaccines in comparison to conventional BCG. Our fortuitum (6) and Mycobacterium bovis Bacillus Calmette–Guérin data reveal a distinct immune dysfunction that is associated with di- (BCG) (9). However, the precise defects that predispose the dia- minished recognition of mycobacterial antigens in T2D. More impor- tantly, we provide compelling evidence that mucosal delivery of betic lung to TB disease remain unknown. Mycobacterium tuberculosis While the immunological correlates of TB protection are not recombinant BCG strains expressing the + (Mtb) ESX-1 secretion system (BCG::RD1 and BCG::RD1 ESAT-6 well defined, the role of CD4 T cells in Mtb immunity is well Δ92–95) are safe and confer superior immunity against aerosol Mtb established in animal models and TB patients. Depletion of Th1 infection in the context of T2D. Our findings suggest that the remark- cells results in early disease reactivation from LTBI as seen in able anti-TB immunity by these recombinant BCG strains is achieved HIV patients (10). However, accumulating evidence suggests a + via augmenting the numbers and functional capacity of antigen pre- substantive role for CD4 T cell-independent protective immu- senting cells in the lungs of diabetic mice. nity (11). For example, we and others have recently shown that tuberculosis | type 2 diabetes | vaccines | immunity Significance uberculosis (TB) is caused by infection with Mycobacterium Tuberculosis (TB) susceptibility and disease are significantly Ttuberculosis (Mtb) and is the leading infectious cause of death exacerbated in people with type 2 diabetes. The underlying globally. Approximately 10 million new TB cases were reported in mechanisms are incompletely understood, and it is not known 2018 with a further 1.7 billion people worldwide latently infected if new TB vaccine candidates will be safe and provide protec- and at risk for reactivation (1). Despite recent advances in diag- tion in the context of diabetes. Using a long-term diet-induced nostics, treatment options, and control measures, TB still kills an murine model of type 2 diabetes, we demonstrate that in- estimated 1.5 million people each year (1). Reactivation of latent creased susceptibility to TB is caused by impaired mycobacterial TB infection (LTBI) is strongly associated with comorbid immu- recognition and killing in the diabetic lung. Importantly, we nosuppressing conditions, most notably HIV coinfection/AIDS show that mucosal vaccination of diabetic mice with Bacillus and diabetes mellitus (DM) (2). It is now recognized that the in- Calmette–Guérin (BCG) strains expressing the ESX-1 secretion fluence of DM, particularly type 2 diabetes (T2D) on TB burden is system from Mycobacterium tuberculosis can overcome this greater than HIV coinfection, because of its higher prevalence defect and provide superior immunity against TB. Our data – (∼463 million people currently live with DM and the numbers are warrant a consideration of ESX-1 containing BCG strains as expected to escalate to 700 million by 2045) (3), with the majority effective TB vaccines in older individuals and diabetics. of diabetics living in TB endemic countries. Based on recent Author contributions: H.D.S., N.K., and A.K. designed research; H.D.S., V.M., M.A.A., and metaanalyses, individuals with DM have a three- to fourfold in- A.K. performed research; R.B. contributed new reagents/analytic tools; H.D.S., M.M.C., creased risk of developing TB while ∼10% of TB patients have M.A.F., N.K., B.G., C.M.R., L.H., and A.K. analyzed data; H.D.S. and A.K. wrote the paper; comorbid DM (4). Furthermore, the risk of reactivation of LTBI is and R.B., N.K., B.G., C.M.R. and L.H. provided intellectual input. significantly increased in TB/T2D comorbid patients (5). TB/T2D The authors declare no competing interest. comorbidity is not limited to low- to middle-income countries but This article is a PNAS Direct Submission. also exists in developed nations. As a result, TB/T2D comorbidity Published under the PNAS license. poses a significant challenge to the global eradication of TB. 1To whom correspondence may be addressed. Email: [email protected]. Although the mechanisms underlying this increased suscepti- This article contains supporting information online at https://www.pnas.org/lookup/suppl/ bility to TB are not well understood, multiple animal models of doi:10.1073/pnas.2003235117/-/DCSupplemental. DM, including T2D, show defective innate immune recognition First published August 10, 2020. 20848–20859 | PNAS | August 25, 2020 | vol. 117 | no. 34 www.pnas.org/cgi/doi/10.1073/pnas.2003235117 Downloaded by guest on September 27, 2021 vaccine-induced CD4+ T cells are not necessary to prevent the 2,203 ± 62.26, P < 0.0001; Fig. 1D), key metabolic features as- reactivation of LTBI in murine (12) and nonhuman primate sociated with the development of T2D. (NHP) models (11). Understanding which immune responses To determine if the EDD-fed T2D mice are more prone to truly correlate with protection will be critical for the develop- Mtb infection, we exposed T2D and control mice to a very-low ment of an effective TB vaccine. BCG, the only approved TB dose (10 to 20 colony-forming units [CFUs]) of Mtb H37Rv. vaccine to date does not provide sufficient protection against There was no difference in lung Mtb burden between control and pulmonary TB in adults (13). Current experimental TB vaccine T2D mice at 1 d after Mtb challenge (Fig. 1E), indicating that strategies include: boosting BCG with improved and more im- bacterial inhalation is not affected by T2D and all mice received munogenic recombinant BCG (rBCG) strains; live attenuated a comparable dose. At 45 d after Mtb challenge, however, T2D Mtb vaccines; and subunit vaccines that are safe to use in im- mice displayed significantly higher lung and spleen CFU loads munocompromised individuals (14). There is also renewed in- (Fig. 1F) accompanied by increased pathological damage to the terest in intravenous (i.v.) (15) and mucosal delivery of TB lung tissue (Fig. 1G and SI Appendix, Fig. S1). Collectively, these vaccines, including BCG, primarily due to the increased pro- data demonstrate that the diet-induced murine model of T2D tection afforded by pulmonary resident memory T cells (TRM) mimics the cardinal features of human T2D and the increased (16). rBCG strains engineered to incorporate immunodominant susceptibility to aerosol Mtb infection, further confirming the Mtb regions, such as the virulence-associated ESX-1 locus, cy- appropriateness of this model to study TB/T2D comorbidity. tokines, toxin-derived antigens, and genes important for antigen Mtb presentation enhance and broaden the vaccine-induced immune Compositional Changes in the Lung Microbiota following response (17). Furthermore, strategies that allow the vaccine Infection. The resident microbiota has a pivotal role in the on- strain to reach the cytosol via the incorporation of phagosome set of T2D and its plethora of complications while perturbed perforating molecules, such as the ESX-1 system (18) or lister-
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