5-Lipoxygenase Activity Increases Susceptibility to Experimental Paracoccidioides brasiliensis Infection

Abstract

Paracoccidioidomycosis (PCM) is a systemic mycosis caused by the thermodimorphic fungus Paracoccidioides brasiliensis. Leukotrienes and lipoxins are lipid mediators produced after 5-lipoxygenase (5-LO) activation that exhibit pro-and anti-inflammatory roles, respectively. Here, we have investigated the contribution of 5-LO enzymatic activity in PCM using an experimental model of P. brasiliensis infection. B6.129 wild-type (B6.129) and 5-LO-deficient (5-LO ؊/؊ ) mice were intravenously inoculated with a virulent strain of P. brasiliensis (Pb18), and the survival rate of the infected mice was investigated on different days after yeast infection. 5-LO ؊/؊ mice exhibited an increased survival rate associated with a decreased number of CFU. The resistance of 5-LO ؊/؊ during PCM was associated with augmented nitric oxide (NO) production and the formation of compact granulomas. In addition, the absence of 5-LO was associated with a diminished number of CD4 ؉ CD25 ؉ regulatory T cells, higher levels of gamma interferon and interleukin-12, and increased T-bet (a T-box transcription factor that directs Th1 lineage commitment) mRNA levels in the lungs. Taken together, our results show for the first time that 5-LO enzymatic activity increases susceptibility to P. brasiliensis, suggesting that this pathway may be a potential target for therapeutic intervention during PCM.

The Pivotal Role of 5-Lipoxygenase-Derived LTB4 in Controlling Pulmonary Paracoccidioidomycosis

“…Mice treated with the 5-LO inhibitor (MK 886) presented increased fungal recovery, showing that endogenous production of leukotrienes is associated with a protective immune response. Our study differs in several aspects to the first one [28], especially regarding the route of infection. Our murine experimental model used the intratracheal route that better mimics the infection in the human host.…”

“…The first one showed that levels of leukotrienes and lipoxins were increased in WT-infected mice and that 5-LO −/− mice exhibited diminished fungal growth and increased survival rate compared to WT mice. These data indicate that 5-LO derived products might have a critical role in the exacerbation and severity of PCM [28]. Another study investigated the involvement of leukotrienes in the early stages of experimental PCM in selected mouse lines endowed with maximal or minimal acute inflammatory reactivity, and designated AIRmax and AIRmin, respectively [29].…”

“…However, two recent studies published reported conflicting participation of 5-LO in P. brasiliensis infection. Although 5-LO enzymatic activity was shown to enhance susceptibility during experimental P. brasiliensis infection [28], Balderramas and colleagues demonstrated that leukotriene production was associated with a protective response during the early stages of P. brasiliensis infection in the lungs. LTB 4 was shown to induce influx and activation of phagocytes [29].…”

Mammalian lipoxygenases and their biological relevance

“…When Alox5 deficient mice and corresponding wild-type controls were intravenously inoculated with P. brasiliensis they exhibited an increased survival rate [401]. The disease resistance was associated with augmented nitric oxide production, reduced number of CD4(+)-CD25(+) regulatory T cells and higher levels of gamma interferon as well as interleukin-12 levels in the lungs.…”

Severe Paracoccidioidomycosis in a 14-Year-Old Boy

“…Mice deficient in the 5-lipoxygenase (5-LO) enzyme, necessary for LTB production, are resistant to P. brasiliensis infection and present reduced number of fungal cells in affected tissues and organs [40].…”