Induction and Role of Indoleamine 2,3 Dioxygenase in Mouse Models of Influenza A Virus Infection

Abstract

Influenza infection stimulates protective host immune responses but paradoxically enhances lung indoleamine 2,3 dioxygenase (IDO) activity, an enzyme that suppresses helper/effector T cells and activates Foxp3-lineage regulatory CD4 T cells (Tregs). Influenza A/PR/8/34 (PR8) infection stimulated rapid elevation of IDO activity in lungs and lung-draining mediastinal lymph nodes (msLNs). Mice lacking intact IDO1 genes (IDO1-KO mice) exhibited significantly lower morbidity after sub-lethal PR8 infection, and genetic or pharmacologic IDO ablation led to much faster recovery after virus clearance. More robust influenza-specific effector CD8 T cell responses manifested in lungs of PR8-infected IDO1-KO mice, though virus clearance rates were unaffected by IDO ablation. Similar outcomes manifested in mice infected with a less virulent influenza A strain (X31). IDO induction in X31-infected lungs was dependent on IFN type II (IFNγ) signaling and was restricted to non-hematopoietic cells, while redundant IFN type 1 or type II signaling induced IDO exclusively in hematopoietic cells from msLNs. Memory T cells generated in X31-primed IDO1-KO mice protected mice from subsequent challenge with lethal doses of PR8 (100×LD50). However recall T cell responses were less robust in lung interstitial tissues, and classic dominance of TCR Vβ8.3 chain usage amongst memory CD8+ T cells specific for influenza nucleoprotein (NP366) did not manifest in IDO1-KO mice. Thus, influenza induced IDO activity in lungs enhanced morbidity, slowed recovery, restrained effector T cell responses in lungs and shaped memory T cell repertoire generation, but did not attenuate virus clearance during primary influenza A infection.

Role of indoleamine 2,3-dioxygenase in health and disease

“…An initial study in 1979 by Yoshida et al [527] reported the robust induction of IDO1 and the Kyn pathway in the lungs of influenza virus-infected mice, a finding subsequently replicated by others [475, [528][529][530]. Recent data indicate that lung influenza infection elicits IFN-independent IDO1 expression in haematopoietic cells of the draining lymph node, whereas IDO1 expression in the non-haematopoietic epithelial cells of the lung is IFNγ -dependent [530].…”

“…Although influenza virus was reported to induce the robust expression of IDO1 within the lung of infected animals back in 1979 [527], insights into the potential role of the enzyme in influenza infection have only recently been forthcoming. In murine influenza, inhibition of IDO1 activity in wild-type mice with 1-DL-MT or infection of IDO1 −/− mice, enhanced the primary immune response to infection by increasing the production of macrophage-derived pro-inflammatory cytokines, promoting CD4 + and CD8 + T-cell function, as well as Th1 responses [529,530]. Secondary immune responses are also affected, as 1-DL-MT treatment or Ido1 gene deficiency also resulted in elevated effector CD4 + Th1 and Th17 responses, increased the number of effector memory CD8 + T-cells, altered the memory CD8 + T-cell repertoire and decreased numbers of CTLA-4-expressing Tregs [529,530,553].…”

“…IDO1 inhibition is also associated with improved tissue repair in influenza [553]. However, despite these clear enhancements of primary and secondary immune responses, there is no apparent difference in lung viral burden or morbidity recorded between untreated and 1-DL-MT-or 1-D-MT-treated wild-type mice [529,530,553], although infected IDO1 −/− mice exhibit improved survival and more rapid recovery from influenza virus infection [530]. These discrepant lethality results between the 1-MT and IDO1 −/− studies may be reconciled by the fact that, although the level of replicating virus in the lung declines by day 6 and is below the level of detection by day 7, 1-MT treatment does not inhibit IDO1 activity, as indexed by the Kyn/L-Trp ratio, until day 10 post-infection [529].…”

Effects of Interferons and Viruses on Metabolism

“…Hence, Trp depletion inhibits T cell immunity and, moreover, the oxidation of Trp by IDO1 generates Kyn derivatives, which promote T cell tolerance by induction of regulatory T cells (121) (Figure 4). Therefore, mice lacking IDO1 exhibit significantly lower morbidity after sub-lethal influenza A infection by generating a stronger influenza-specific effector CD8 T cell response, though viral clearance rates are unaffected by IDO1 ablation (127). Similarly, genetic ablation of IDO1 or chemical inhibition with 1-methyl- d - l -tryptophan suppresses viral replication of murine leukemia virus in vivo and upregulates type I IFN production (128).…”

Multi-Omics Studies towards Novel Modulators of Influenza A Virus–Host Interaction

“…Interestingly, 41 of the 199 druggable cellular factors were shown to be implicated in IAV infection (Table S2) [10,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,...…”