Helminth-induced arginase-1 exacerbates lung inflammation and disease severity in tuberculosis

• Published in: The Journal of clinical investigation Vol. 125; no. 12; pp. 4699 - 4713
• Main Authors: Monin, Leticia, Griffiths, Kristin L., Lam, Wing Y., Gopal, Radha, Kang, Dongwan D., Ahmed, Mushtaq, Rajamanickam, Anuradha, Cruz-Lagunas, Alfredo, Zúñiga, Joaquín, Babu, Subash, Kolls, Jay K., Mitreva, Makedonka, Rosa, Bruce A., Ramos-Payan, Rosalio, Morrison, Thomas E., Murray, Peter J., Rangel-Moreno, Javier, Pearce, Edward J., Khader, Shabaana A.
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.12.2015
• Subjects: Animals; Antigens; Arginase - blood; Biomedical research; Children & youth; Colleges & universities; Complications and side effects; Development and progression; Disease susceptibility; Female; Genetic aspects; Granuloma - enzymology; Granuloma - microbiology; Granuloma - parasitology; Granuloma - pathology; Helminthiasis; Humans; Infections; Inflammation; Laboratory animals; Lung - metabolism; Lung - microbiology; Lung - parasitology; Lung - pathology; Lungs; Lymphocytes; Macrophages - enzymology; Macrophages - pathology; Male; Medical research; Medicine, Experimental; Mice; Mice, Transgenic; Mycobacterium; Mycobacterium tuberculosis; Neutrophils; Schistosoma mansoni; Schistosomiasis mansoni - blood; Schistosomiasis mansoni - microbiology; Schistosomiasis mansoni - pathology; Tuberculosis; Tuberculosis, Pulmonary - blood; Tuberculosis, Pulmonary - parasitology; Tuberculosis, Pulmonary - pathology
• ISSN: 0021-9738; 1558-8238; 1558-8238
• DOI: 10.1172/JCI77378

Parasitic helminth worms, such as Schistosoma mansoni, are endemic in regions with a high prevalence of tuberculosis (TB) among the population. Human studies suggest that helminth coinfections contribute to increased TB susceptibility and increased rates of TB reactivation. Prevailing models suggest that T helper type 2 (Th2) responses induced by helminth infection impair Th1 immune responses and thereby limit Mycobacterium tuberculosis (Mtb) control. Using a pulmonary mouse model of Mtb infection, we demonstrated that S. mansoni coinfection or immunization with S. mansoni egg antigens can reversibly impair Mtb-specific T cell responses without affecting macrophage-mediated Mtb control. Instead, S. mansoni infection resulted in accumulation of high arginase-1-expressing macrophages in the lung, which formed type 2 granulomas and exacerbated inflammation in Mtb-infected mice. Treatment of coinfected animals with an antihelminthic improved Mtb-specific Th1 responses and reduced disease severity. In a genetically diverse mouse population infected with Mtb, enhanced arginase-1 activity was associated with increased lung inflammation. Moreover, in patients with pulmonary TB, lung damage correlated with increased serum activity of arginase-1, which was elevated in TB patients coinfected with helminths. Together, our data indicate that helminth coinfection induces arginase-1-expressing type 2 granulomas, thereby increasing inflammation and TB disease severity. These results also provide insight into the mechanisms by which helminth coinfections drive increased susceptibility, disease progression, and severity in TB.