Leptospirosis is an important zoonosis and has a worldwide impact on public health. This paper will discuss both the role of immunogenic and pathogenic molecules during leptospirosis infection and possible new targets for immunotherapy against leptospira components. Leptospira, possess a wide variety of mechanisms that allow them to evade the host immune system and cause infection. Many molecules contribute to the ability of Leptospira to adhere, invade, and colonize. The recent sequencing of the Leptospira genome has increased our knowledge about this pathogen. Although the virulence factors, molecular targets, mechanisms of inflammation, and signaling pathways triggered by leptospiral antigens have been studied, some questions are still unanswered. Toll-like receptors (TLRs) are the primary sensors of invading pathogens. TLRs recognize conserved microbial pattern molecules and activate signaling pathways that are pivotal to innate and adaptive immune responses. Recently, a new molecular target has emerged—the Na/K-ATPase—which may contribute to inflammatory and metabolic alteration in this syndrome. Na/K-ATPase is a target for specific fatty acids of host origin and for bacterial components such as the glycolipoprotein fraction (GLP) that may lead to inflammasome activation. We propose that in addition to TLRs, Na/K-ATPase may play a role in the innate response to leptospirosis infection.

Background Integrase strand transfer inhibitor (INSTI)-based regimens are recommended for first-line therapy in HIV-2. Nonetheless, dolutegravir (DTG) clinical trial data is lacking. Methods We conducted a phase II, single arm, open-label trial to evaluate the safety and efficacy of a triple therapy regimen including DTG, in persons with HIV-2 (PWHIV-2) in Portugal. Treatment-naïve adults were recruited to receive DTG in combination with two nucleoside reverse transcriptase inhibitors (NRTIs). Treatment efficacy was evaluated by the proportion of subjects achieving a plasma viral load (pVL) <40 copies/mL and/or by the change from baseline in CD4+T cell count and in CD4/CD8 ratio at week 48. Results A total of 30 subjects were enrolled [22 women, median age 55 years-old]. At baseline, 17 (56.7%) individuals were viremic [median pVL 190 copies/mL; interquartile range (IQR): 99-445 copies/mL]. The median CD4 count was 438 cells/μL (IQR: 335-605) and CD4/CD8 ratio was 0.8. During follow-up, 3 subjects discontinued the study. At week 48, all participants (27) had pVL<40 copies/mL. No virological failures were observed. Mean changes of CD4 count and CD4/CD8 ratio at week 48 were of + 95.59 (95%CI: 28.05-163.14) cells/µL and +0.32 (95%CI: 0.19-0.46). The most common drug-related adverse events were headache and nausea. One participant discontinued due to central nervous system symptoms. No serious adverse events were reported. Conclusions DTG plus two NRTIs is safe and effective as first-line treatment for PWHIV-2 with a tolerability profile previously known. No virological failures were observed which suggest a high potency of DTG in HIV-2 as occurs in HIV-1.

The role of both exogenously administered and endogenously generated bradykinin (BK) on LPS‐induced eosinophil accumulation in the mice pleural cavity was investigated by means of treatment with BK selective receptor agonists/antagonists and captopril. Intrathoracic (i.t.) injection of LPS (250 ng cavity−1) induced eosinophil influx at 24 h as previously described (Bozza et al., 1993). Pretreatment with the B1 receptor antagonist des‐Arg9‐[leu‐8]BK (0.025 and 0.25 nmol cavity−1) showed no effect on this phenomenon, whereas pretreatment with the B2 receptor antagonists, NPC 17731 (0.025 and 0.25 nmol cavity−1) or HOE 140 (2.5 nmol cavity−1), increased LPS‐induced eosinophil influx. Accordingly, pretreatment with captopril at 10 mg kg−1 i.p., inhibited eosinophil infiltration induced by LPS in the pleural cavity, suggesting that endogenous BK is down‐regulating LPS‐induced eosinophil accumulation. BK administered at 15 and 25 nmol cavity−1, i.t. or i.p. also inhibited LPS‐induced eosinophil accumulation. BK alone had no effect on the basal number of leucocytes in the pleural or peritoneal cavity in doses up to 25 nmol cavity−1. Nevertheless, when injected at doses of 50 and 100 nmol cavity−1 BK induced leucocyte influx characterized by neutrophil and eosinophil accumulation at 24 h. Similarly to what was observed with BK, a specific B2 receptor agonist, Tyr8BK, administered at 0.25 nmol cavity−1 i.p., significantly inhibited the eosinophil influx induced by LPS. The mechanism by which B2 receptor agonists inhibit LPS‐induced eosinophil accumulation was investigated by pretreating the animals with indomethacin or a selective cyclooxygenase‐2 inhibitor, NS‐398. Pretreatment with either indomethacin or NS‐398 had no effect on eosinophil influx induced by LPS alone, but those drugs were able to restore the LPS‐induced eosinophil influx in Tyr8BK (0.25 nmol cavity−1) injected mice. In conclusion, endogenously generated bradykinin seems to modulate, through activation of B2 receptors, eosinophil accumulation induced by LPS via a mechanism dependent on prostanoid synthesis. British Journal of Pharmacology (1999) 127, 569–575; doi: