Nitric oxide has a wide variety of regulatory activities, which can affect the chronic host response to infection [2-5]. In the case Cytoskeletal Signaling inhibitor of Mycobacterium avium, the bacteria are not susceptible to the toxic effects of nitric oxide [6], allowing us to probe the role of reactive nitrogen intermediates in regulation of the T-cell response to mycobacterial infection

without the confounding factor of uncontrolled bacterial growth. Nitric oxide acts on physiological systems with effects dependent upon concentration, the relative levels of reactive oxygen radicals and pH [7]. At low concentrations, nitric oxide acts as a signaling molecule, either in a cGMP-dependent or -independent manner, to promote vascular integrity, mediate neurotransmission, and regulate cellular respiration by altering the affinity of cytochrome C for oxygen [7, 8]. At high concentrations, nitric oxide inhibits respiration and causes nitrosative damage Antiinfection Compound Library to proteins, lipid peroxidation, and DNA [9, 10]. The balance between nitric oxide and oxygen radicals is important, as nitric oxide can reduce oxidative stress [11] but also generates peroxynitrite, which is itself damaging [12]. The damage generated by high levels of nitric oxide is detrimental to cells and results in apoptosis [9]. The impact of nitric oxide on the immune response has been extensively analyzed with identification of both positive and negative regulatory roles [13].

In humans, nitric oxide limits IL-2 release and proliferation of T cells via activation of the cGMP-dependent protein kinase, cGK I [14]. In Trypanosoma brucei mouse models, nitric oxide inhibits the accumulation of IL-2- and IFN-γ-producing T cells [15]. In both an in vitro system [16] and a Listeria monocytogenes mouse model [17], the inhibition of nitric oxide synthase (Nos)

results in improved antigen-specific T-cell responses. Nitric oxide also acts as an anti-inflammatory agent by limiting the interaction of leucocytes with the endothelial monolayer [18]. Nitric oxide can drive IL-10-producing regulatory T cells, limit the expansion of Th17 cells [19, 20], and regulate the IL-12 pathway both positively [21] and negatively [22]. Indeed, at low levels, it can augment the generation of Th1 cells by increasing expression of IL-12Rβ2 [23, 24] Carnitine palmitoyltransferase II and augment IFN-γ−mediated signaling [25]. In mycobacterial disease, nitric oxide is essential for the control of Mycobacterium tuberculosis but dispensable for the control of M. avium [4]. It limits the accumulation of activated T cells in the Mycobacterium bovis BCG model [26], the M. tuberculosis model [27], and the M. avium model [6] with an increased IFN-γ response being seen in both M. avium [6] and M. tuberculosis infected nos2−/− mice [28]. Absence of nitric oxide in M. avium infection results in lesions with increased cellularity and collagen deposition [6, 29, 30].