Helminth-induced arginase-1 exacerbates lung inflammation and disease severity in tuberculosis
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
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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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 2

S. mansoni coinfection leads to increased lung pathology, impaired Th1 responses, and increased susceptibility to Mtb infection.

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S. mansoni coinfection leads to increased lung pathology, impaired Th1 ...
S. mansoni–infected (Mtb + Sm) or control Yarg mice (Mtb) were infected with Mtb. (A) On d30 after infection, lung expression of Il4, Il13, Mmp13, and Mpo mRNA relative to Gapdh was determined by RT-PCR. (B) Formalin-fixed, paraffin embedded (FFPE) sections were processed for immunofluorescence using antibodies for Muc5AC and CD3; mucus and glycogen accumulation by the PAS stain and collagen deposition by Gomori’s Trichrome stain are shown. Magnification: ×200. Arrows indicate areas of positive staining. (C–D) Immunofluorescence staining for B220 and CD3 was also performed. Magnification: ×200. The average size of B cell follicles within granulomas (C) and the average area of perivascular T cell cuffing (D) were calculated. (E–F) The percentage of lung IFN-γ– (E) and IL-4–producing activated T cells (CD4+CD44+IFN-γ+ and CD4+CD44+IL-4+, respectively) (F) were determined by flow cytometry. (G) MHCII expression on lung macrophages was determined by flow cytometry. (H) The percentage of ESAT-61–20–specific, IFN-γ–producing cells in the lungs was determined by antigen-driven ELISpot. (I) Lung bacterial burden was determined by plating. n = 4–9 mice per group. Lungs of all mice were included in the analysis; one representative image per group is shown. #P = 0.0616, *P ≤ 0.05, ***P ≤ 0.001; unpaired, 2-tailed Student’s t test (A and C–I). Results are representative of 2 independent experiments.