Helminth-induced arginase-1 exacerbates lung inflammation and disease severity in tuberculosis.
Monin, L.; Griffiths, K.L.; Lam, W.Y.; Gopal, R.; Kang, D.D.; Ahmed, M.; Anuradha, R.; Cruz-Lagunas, A.; Zúñiga, J.; Babu, S.; Kolls, J.K.; Mitreva, M.; Rosa, B.A.; Ramos-Payan, R.; Morrison, T.E.; Murray, P.J.; Rangel-Moreno, J.; Pearce, E.J.; Khader, S.A.
Journal of Clinical Investigation; 2015; 125; 4699-4713.
Abstract: 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.
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