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

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.

SUBMITTER: Monin L

PROVIDER: S-EPMC4665786 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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

Monin Leticia L Griffiths Kristin L KL Lam Wing Y WY Gopal Radha R Kang Dongwan D DD Ahmed Mushtaq M Rajamanickam Anuradha A Cruz-Lagunas Alfredo A Zúñiga Joaquín J Babu Subash S Kolls Jay K JK Mitreva Makedonka M Rosa Bruce A BA Ramos-Payan Rosalio R Morrison Thomas E TE Murray Peter J PJ Rangel-Moreno Javier J Pearce Edward J EJ Khader Shabaana A SA

The Journal of clinical investigation 20151116 12

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 infecti ...[more]

PMID: 26571397

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

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

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