Journal Article

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

Kang, Dongwan D., Ahmed, Mushtaq, Rangel-Moreno, Javier, Pearce, Edward J., Lam, Wing Y., Zúñiga, Joaquín, Babu, Subash, Kolls, Jay K., Morrison, Thomas E., Khader, Shabaana A., Monin, Leticia, Murray, Peter J., Ramos-Payan, Rosalio, Griffiths, Kristin L., Gopal, Radha, Mitreva, Makedonka, Rosa, Bruce A., Rajamanickam, Anuradha, Cruz-Lagunas, Alfredo

2015

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: 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