Harnessing Innate Immunity to Treat <i>Mycobacterium tuberculosis</i> Infections: Heat-Killed <i>Caulobacter crescentus</i> as a Novel Biotherapeutic
Nancy Gupta,
Satish Vedi,
Saurabh Garg,
Eric Loo,
Jie Li,
Dennis Y. Kunimoto,
Rakesh Kumar,
Babita Agrawal
Affiliations
Nancy Gupta
Department of Laboratory Medicine and Pathology, Faculty of Medicine and Dentistry, College of Health Sciences, University of Alberta, Edmonton, AB T6G 1C9, Canada
Satish Vedi
Department of Laboratory Medicine and Pathology, Faculty of Medicine and Dentistry, College of Health Sciences, University of Alberta, Edmonton, AB T6G 1C9, Canada
Saurabh Garg
Department of Laboratory Medicine and Pathology, Faculty of Medicine and Dentistry, College of Health Sciences, University of Alberta, Edmonton, AB T6G 1C9, Canada
Eric Loo
Department of Surgery, Faculty of Medicine and Dentistry, College of Health Sciences, University of Alberta, Edmonton, AB T6G 2S2, Canada
Jie Li
Department of Surgery, Faculty of Medicine and Dentistry, College of Health Sciences, University of Alberta, Edmonton, AB T6G 2S2, Canada
Dennis Y. Kunimoto
Department of Medicine, Faculty of Medicine and Dentistry, College of Health Sciences, University of Alberta, Edmonton, AB T6G 2R7, Canada
Rakesh Kumar
Department of Laboratory Medicine and Pathology, Faculty of Medicine and Dentistry, College of Health Sciences, University of Alberta, Edmonton, AB T6G 1C9, Canada
Babita Agrawal
Department of Surgery, Faculty of Medicine and Dentistry, College of Health Sciences, University of Alberta, Edmonton, AB T6G 2S2, Canada
Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), is a serious and devastating infectious disease worldwide. Approximately a quarter of the world population harbors latent Mtb infection without pathological consequences. Exposure of immunocompetent healthy individuals with Mtb does not result in active disease in more than 90% individuals, suggesting a defining role of host immunity to prevent and/or clear early infection. However, innate immune stimulation strategies have been relatively underexplored for the treatment of tuberculosis. In this study, we used cell culture and mouse models to examine the role of a heat-killed form of a non-pathogenic microbe, Caulobacter crescentus (HKCC), in inducing innate immunity and limiting Mtb infection. We also examined the added benefits of a distinct chemo-immunotherapeutic strategy that incorporates concurrent treatments with low doses of a first-line drug isoniazid and HKCC. This therapeutic approach resulted in highly significant reductions in disseminated Mtb in the lungs, liver, and spleen of mice compared to either agent alone. Our studies demonstrate the potential of a novel innate immunotherapeutic strategy with or without antimycobacterial drugs in controlling Mtb infection in mice and open new avenues for the treatment of tuberculosis in humans.