Helminth-induced arginase-1 exacerbates lung inflammation and disease severity in tuberculosis
Leticia Monin, … , Edward J. Pearce, Shabaana A. Khader
Leticia Monin, … , Edward J. Pearce, Shabaana A. Khader
Published November 16, 2015
Citation Information: J Clin Invest. 2015;125(12):4699-4713. https://doi.org/10.1172/JCI77378.
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Research Article Immunology

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.

Authors

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

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Figure 4

Absence of arginase-1 in lung macrophages reverses lung pathology upon coinfection.

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Absence of arginase-1 in lung macrophages reverses lung pathology upon c...
WT BMC or Tie2-Cre Arg1fl/fl BMC mice were S. mansoni/Mtb coinfected (Mtb + Sm) or infected with Mtb alone (Mtb). (A) On d25 after infection, lung bacterial burden was determined by plating. (B) Pulmonary inflammation was assessed on formalin-fixed, paraffin embedded (FFPE) lung sections stained with H&E. Magnification: ×100. (C) Total area occupied by inflammatory lesions per lobe was quantified. (D) FFPE sections were processed for immunofluorescence using antibodies for B220 and CD3. Magnification: ×200. The average size of B cell follicles within granulomas was determined. (E) The average area of perivascular T cell cuffing in B220- and CD3-stained sections was calculated. (F) FFPE sections were stained with antibodies specific for arginase-1, iNOS, and F4/80. Magnification: ×200. The number of high arginase-1–expressing F4/80+ cells per ×200 field was determined. n = 3–10 mice per group. Lungs of all mice were included in the analysis; one representative image per group is shown. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001. ND, not detectable. One-way ANOVA with post-hoc Tukey (A and C) and unpaired, 2-tailed Student’s t tests were used (D–F).