Protective effect of picolinic acid on mice intracerebrally infected with lethal doses of Candida albicans

Blasi, Elisabetta; Mazzolla, Rosanna; Pitzurra, Lucia; Barluzzi, Roberta; Bistoni, Francesco

doi:10.1128/aac.37.11.2422

Cited by 28 publications

(22 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Therefore, more than a reduced tryptophan availability and an increased level of toxic metabolites, the growth restriction of IDO against Candida, a tryptophan prototrophic strain (14), appears to be the result of an action on the oxidant-antioxidant state of effector cells. Actually, a product of tryptophan catabolism, picolinic acid, has protective effects in mice with candidiasis (39). Similar to what was observed in DCs (20 -22), IDO functional activity in PMNs was regulated by CTLA-4-Ig acting on B7-1 molecules, a finding that expands upon the importance of the B7-CTLA-4 coreceptor pathway in conditioning innate and adaptive immune responses (14).…”

Section: Discussionsupporting

confidence: 60%

A Crucial Role for Tryptophan Catabolism at the Host/Candida albicansInterface

Bozza

Fallarino

Pitzurra

et al. 2005

The Journal of Immunology

141

108

View full text Add to dashboard Cite

By mediating tryptophan catabolism, the enzyme indoleamine 2,3-dioxygenase (IDO) has a complex role in immunoregulation in infection, pregnancy, autoimmunity, transplantation, and neoplasia. We hypothesized that IDO might affect the outcome of the infection in mice infected with Candida albicans by virtue of its potent regulatory effects on inflammatory and T cell responses. IDO expression was examined in mice challenged with the fungus along with the consequences of its blockade by in vivo treatment with an enzyme inhibitor. We found that IDO activity was induced at sites of infection as well as in dendritic cells and effector neutrophils via IFN-γ- and CTLA-4-dependent mechanisms. IDO inhibition greatly exacerbated infection and associated inflammatory pathology as a result of deregulated innate and adaptive/regulatory immune responses. However, a role for tryptophan catabolism was also demonstrated in a fungus-autonomous fashion; its blockade in vitro promoted yeast-to-hyphal transition. These results provide novel mechanistic insights into complex events that, occurring at the fungus/pathogen interface, relate to the dynamics of host adaptation to the fungus. The production of IFN-γ may be squarely placed at this interface, where IDO activation probably exerts a fine control over fungal morphology as well as inflammatory and adaptive antifungal responses.

show abstract

Section: Discussionsupporting

confidence: 60%

A Crucial Role for Tryptophan Catabolism at the Host/Candida albicansInterface

Bozza

Fallarino

Pitzurra

et al. 2005

The Journal of Immunology

141

108

View full text Add to dashboard Cite

show abstract

“…PA is also tumoricidal in vivo (29), an effect that is related to the induction of macrophage-mediated cytostatic activity (30). The idea that PA plays a role in immune mechanisms is strengthened by the observation that mice treated with PA have enhanced levels of mRNA for IL-1 and TNF-␣ and higher resistance to Candida albicans (31). In vitro studies with macrophages confirmed that PA is a modulator of macrophage functions because it costimulates macrophage activation and enhances the antitumor activity of peritoneal macrophages treated with IFN-␥ (32).…”

mentioning

confidence: 92%

Macrophage Control of Mycobacterial Growth Induced by Picolinic Acid Is Dependent on Host Cell Apoptosis

Pais

Appelberg

2000

The Journal of Immunology

View full text Add to dashboard Cite

The effects of picolinic acid (PA) on the intramacrophagic growth of Mycobacterium avium were studied. PA reduced M. avium growth inside mouse macrophages and led to a complete control of mycobacterial growth when added together with IFN-γ. The mechanism involved did not require TNF-α, NO, or the respiratory burst, and was not dependent on either iron or zinc withholding. The mycobacteriostatic activity of the macrophages was associated with the induction of morphological changes that culminated in apoptosis at day 4 of treatment. PA alone induced apoptosis in macrophages, and this effect was increased by IFN-γ treatment. Apoptosis at day 4 of infection was reduced by inhibiting macrophage activation with the prostaglandin 15 deoxy-prostaglandin J2 or by treating the cells with the antioxidant N-acetylcysteine. Mycobacterial growth was partially restored in macrophages treated with PA and IFN-γ when 15 deoxy-prostaglandin J2 was added, concomitant with a delay in apoptosis. N-Acetylcysteine or glutathione could also completely revert the mycobacteriostatic effects of PA or PA plus IFN-γ.

show abstract

“…The induction of anti-M. avium activity was closely associated with the induction of apoptosis which occurred over a protracted period of a few days. PA is also a co-stimulator of macrophage tumoricidal and antimicrobial activities (Blasi et al, 1993;Leuthauser et al, 1982;Ruffmann et al, 1984;Varesio et al, 1990). …”

Section: Introductionmentioning

confidence: 99%

Induction of Mycobacterium avium growth restriction and inhibition of phagosome–endosome interactions during macrophage activation and apoptosis induction by picolinic acid plus IFNγ

Pais¹,

Appelberg²

2004

Microbiology

View full text Add to dashboard Cite

Treatment of mouse macrophages with picolinic acid (PA) and c-interferon (IFNc) led to the restriction of Mycobacterium avium proliferation concomitant with the sequential acquisition of metabolic changes typical of apoptosis, mitochondrial depolarization, annexin V staining and caspase activation, over a period of up to 5 days. However, triggering of cell death by ATP, staurosporine or H 2 O 2 failed to affect mycobacterial viability. In contrast to untreated macrophages where extensive interactions between phagosomes and endosomes were observed, phagosomes from treated macrophages lost the ability to acquire endosomal dextran. N-Acetylcysteine was able to revert both the anti-mycobacterial activity of treated macrophages as well as the block in phagosome-endosome interactions. The treatment, however, induced only a minor increase in the acquisition of lysosomal markers, namely Lamp-1, and did not increase to any great extent the acidification of the phagosomes. These data thus suggest that the anti-mycobacterial activity of PA and IFNc depends on the interruption of intracellular vesicular trafficking, namely the blocking of acquisition of endosomal material by the microbe. INTRODUCTIONMycobacterium avium is an opportunistic pathogen that infects patients suffering from local or systemic deficiencies of the immune system (Falkinham, 1996). Resistance to infection is dependent on both innate mechanisms and acquired immunity through the development of antigenspecific CD4 + T cells (Appelberg, 1994;Holland, 1996). M. avium replicates inside the macrophage and is particularly resistant to the oxidative antimicrobial mechanisms of this phagocyte (Gomes & Appelberg, 2002;Gomes et al., 1999a). Like other pathogenic mycobacteria, M. avium has evolved survival strategies that interfere with the normal intracellular trafficking of vesicular compartments. After being internalized by macrophages, mycobacteria inhibit the fusion of the vacuole they inhabit with lysosomes, thus blocking maturation of the phagosomes into phagolysosomes and proliferating in vacuoles with early endosomal characteristics (Armstrong & d'Arcy-Hart, 1971;Clemens & Horwitz, 1995;Frehel et al., 1986;Russell et al., 1997). Several mechanisms associated with this inhibition have been described, such as reduced phagosomal acidification (Crowle et al., 1991;Sturgill-Koszycki et al., 1994;de Chastellier et al., 1995) due to exclusion of the vacuolar H + -ATPase , altered signalling pathways (Malik et al., 2001;Fratti et al., 2003), interference with the recycling of Rab proteins (Via et al., 1997), retention of the actin-binding coronin/TACO protein (Ferrari et al., 1999; see also Schuller et al., 2001, for a critical reappraisal of this issue), disorganization of the actin filament network (Guérin & de Chastellier, 2000) and tight apposition of the membrane vacuole to the surface of the pathogen, leading to altered exchange of fusion factors (de Chastellier & Thilo, 1997). However, mycobacterial phagosomes keep their ability to interact extensively wi...

show abstract

Protective effect of picolinic acid on mice intracerebrally infected with lethal doses of Candida albicans

Cited by 28 publications

References 29 publications

A Crucial Role for Tryptophan Catabolism at the Host/Candida albicansInterface

A Crucial Role for Tryptophan Catabolism at the Host/Candida albicansInterface

Macrophage Control of Mycobacterial Growth Induced by Picolinic Acid Is Dependent on Host Cell Apoptosis

Induction of Mycobacterium avium growth restriction and inhibition of phagosome–endosome interactions during macrophage activation and apoptosis induction by picolinic acid plus IFNγ

Contact Info

Product

Resources

About