Anthelmintic Therapy Modifies the Systemic and Mycobacterial Antigen-Stimulated Cytokine Profile in Helminth-Latent Mycobacterium tuberculosis Coinfection

Abstract

Helminth infections are known to modulate cytokine responses in latent tuberculosis (LTB). However, very few studies have examined whether this modulation is reversible upon anthelmintic therapy. We measured the systemic and mycobacterial (TB) antigen-stimulated levels of type 1, type 2, type 17, and regulatory cytokines in individuals with LTB and with or without coexistent Strongyloides stercoralis infection before and after anthelmintic therapy. Our data reveal that individuals with LTB and coexistent S. stercoralis infection have significantly lower levels of systemic and TB antigen-stimulated type 1 (gamma interferon [IFN-γ], tumor necrosis factor alpha [TNF-α], and interleukin-2 [IL-2]) and type 17 (IL-17A and/or IL-17F) cytokines and significantly higher levels of systemic but not TB antigen-stimulated type 2 (IL-4 and IL-5) and regulatory (transforming growth factor beta [TGF-β]) cytokines. Anthelmintic therapy resulted in significantly increased systemic levels of type 1 and/or type 17 cytokines and in significantly decreased systemic levels of type 2 and regulatory (IL-10 and TGF-β) cytokines. In addition, anthelmintic therapy resulted in significantly increased TB antigen-stimulated levels of type 1 cytokines only. Our data therefore confirm that the modulation of systemic and TB antigen-stimulated cytokine responses in S. stercoralis-LTB coinfection is reversible (for the most part) by anthelmintic treatment.

Keywords: Strongyloides; cytokines; helminths; immune responses; tuberculosis.

FIG 1

S. stercoralis infection is associated with diminished systemic levels of type 1 and type 17 cytokines and elevated levels of type 2 cytokines and TGF-β in LTB. (A) The systemic (plasma) levels of type 1 (IFN-γ, TNF-α, IL-2) and type 17 (IL-17A, IL-17F, IL-22) cytokines were measured in LTB individuals with S. stercoralis coinfection (LTB-Ss, n = 60) or without S. stercoralis coinfection (LTB, n = 58). (B) The systemic (plasma) levels of type 2 (IL-4, IL-5, IL-13) and regulatory (IL-10, TGF-β) cytokines were measured in LTB individuals with S. stercoralis coinfection (LTB-Ss, n = 60) or without S. stercoralis coinfection (LTB, n = 58). The results are shown as scatterplots, with each circle representing a single individual and the bar representing the GM. P values were calculated using the Mann-Whitney test with Holm's correction for multiple comparisons.

FIG 2

Treatment modifies the systemic cytokine profile in LTB-S. stercoralis coinfection. (A) The systemic (plasma) levels of type 1 (IFN-γ, TNF-α, IL-2) and type 17 (IL-17A, IL-17F, IL-22) cytokines were measured in LTB-S. stercoralis individuals (n = 60) before (Pre-T) and 6 months after (Post-T) anthelmintic therapy. (B) The systemic (plasma) levels of type 2 (IL-4, IL-5, IL-13) and regulatory (IL-10, TGF-β) cytokines were measured in LTB-S. stercoralis individuals (n = 60) before (Pre-T) and 6 months after (Post-T) anthelmintic therapy. The results are shown as line diagrams, with each line representing a single individual. P values were calculated using the Wilcoxon signed-rank test with Holm's correction for multiple comparisons.

FIG 3

S. stercoralis infection is associated with diminished baseline and/or mycobacterial antigen-stimulated production of type 1 and type 17 cytokines in LTB. The baseline (A) or mycobacterial antigen-stimulated (B) levels (at 18 h) of type 1 (IFN-γ, TNF-α, IL-2) and type 17 (IL-17A, IL-17F, IL-22) cytokines were measured in LTB individuals with S. stercoralis coinfection (LTB-Ss, n = 60) or without S. stercoralis coinfection (LTB, n = 58). The results are shown as scatterplots, with each circle representing a single individual and the bar representing the GM. P values were calculated using the Mann-Whitney test with Holm's correction for multiple comparisons.

FIG 4

Treatment modifies the baseline and mycobacterial antigen-stimulated cytokine profile in LTB-S. stercoralis coinfection. The baseline (A) or mycobacterial antigen-stimulated (B) levels (at 18 h) of type 1 (IFN-γ, TNF-α, IL-2) and type 17 (IL-17A, IL-17F, IL-22) cytokines were measured in LTB-S. stercoralis individuals (n = 60) before (Pre-T) and 6 months after (Post-T) anthelmintic therapy. The results are shown as line diagrams, with each line representing a single individual. P values were calculated using the Wilcoxon signed-rank test with Holm's correction for multiple comparisons.

FIG 5

S. stercoralis infection is associated with diminished baseline but not mycobacterial antigen-stimulated production of regulatory cytokines in LTB. The baseline (A) or mycobacterial antigen-stimulated (B) levels (18 h) of type 2 (IL-4, IL-5, IL-13) and regulatory (IL-10, TGF-β) cytokines were measured in LTB individuals with S. stercoralis coinfection (LTB-Ss, n = 60) or without S. stercoralis coinfection (LTB, n = 58). The results are shown as scatterplots, with each circle representing a single individual and the bar representing the GM. P values were calculated using the Mann-Whitney test with Holm's correction for multiple comparisons.

FIG 6

Treatment does not modify the baseline or mycobacterial antigen-stimulated cytokine profile in LTB-S. stercoralis coinfection. The baseline (A) or mycobacterial antigen-stimulated (B) levels (at 18 h) of type 2 (IL-4, IL-5, IL-13) and type 17 (IL-10, TGF-β) cytokines were measured in LTB-S. stercoralis individuals (n = 60) before (Pre-T) and 6 months after (Post-T) anthelmintic therapy. The results are shown as line diagrams, with each line representing a single individual. P values were calculated using the Wilcoxon signed-rank test with Holm's correction for multiple comparisons.