Current status, challenges and perspectives in the development of vaccines against yellow fever, dengue, Zika and chikungunya viruses.

Emerging and re-emerging viral infections transmitted by insect vectors (arthopode-borne viruses, arbovirus) are a serious threat to global public health. Among them, yellow fever (YFV), dengue (DENV), chikungunya (CHIKV) and Zika (ZIKV) viruses are particularly important in tropical and subtropical regions. Although vector control is one of the most used prophylactic measures against arboviruses, it often faces obstacles, such as vector diversity, uncontrolled urbanization and increasing resistance to insecticides. In this context, vaccines may be the best control strategy for arboviral diseases. Here, we provide a general overview about licensed vaccines and the most advanced vaccine candidates against YFV, DENV, CHIKV and ZIKV. In particular, we highlight vaccine difficulties, the current status of the most advanced strategies and discuss how the molecular characteristics of each virus can influence the choice of the different vaccine formulations.

A scoping review of Chikungunya virus infection: epidemiology, clinical characteristics, viral co-circulation complications, and control.

Chikungunya fever is a mosquito-borne viral illness characterized by a sudden onset of fever associated with joint pains. It was first described in the 1950s during a Chikungunya virus (CHIKV) outbreak in southern Tanzania and has since (re-) emerged and spread to several other geographical areas, reaching large populations and causing massive epidemics. In recent years, CHIKV has gained considerable attention due to its quick spread to the Caribbean and then in the Americas, with many cases reported between 2014 and 2017. CHIKV has further garnered attention due to the clinical diagnostic difficulties when Zika (ZIKV) and dengue (DENV) viruses are simultaneously present. In this review, topical CHIKV-related issues, such as epidemiology and transmission, are examined. The different manifestations of infection (acute, chronic and atypical) are described and a particular focus is placed upon the diagnostic handling in the case of ZIKV and DENV co-circulating. Natural and synthetic compounds under evaluation for treatment of chikungunya disease, including drugs already licensed for other purposes, are also discussed. Finally, previous and current vaccine strategies, as well as the control of the CHIKV transmission through an integrated vector management, are reviewed in some detail.

A proteomic insight into the effects of the immunomodulatory hydroxynaphthoquinone lapachol on activated macrophages.

We report the effect of an immunomodulatory and anti-mycobacterial naphthoquinone, lapachol, on the bi-dimensional patterns of protein expression of toll-like receptor 2 (TLR2)-agonised and IFN-γ-treated THP-1 macrophages. This non-hypothesis driven proteomic analysis intends to shed light on the cellular functions lapachol may be affecting. Proteins of both cytosol and membrane fractions were analysed. After quantification of the protein spots, the protein levels corresponding to macrophages activated in the absence or presence of lapachol were compared. A number of proteins were identified, the levels of which were appreciably and significantly increased or decreased as a result of the action of lapachol on the activated macrophages: cofilin-1, fascin, plastin-2, glucose-6-P-dehydrogenase, adenylyl cyclase-associated protein 1, pyruvate kinase, sentrin-specific protease 6, cathepsin B, cathepsin D, cytosolic aminopeptidase, proteasome ß type-4 protease, tryptophan-tRNA ligase, DnaJ homolog and protein disulphide isomerase. Altogether, the comparative analysis performed indicates that lapachol could be hypothetically causing an impairment of cell migration and/or phagocytic capacity, an increase in NADPH availability, a decrease in pyruvate concentration, protection from proteosomal protein degradation, a decrease in lysosomal protein degradation, an impairment of cytosolic peptide generation, and an interference with NOS2 activation and grp78 function. The present proteomic results suggest issues that should be experimentally addressed ex- and in-vivo, to establish more accurately the potential of lapachol as an anti-infective drug. This study also constitutes a model for the pre-in-vivo evaluation of drug actions.

The hydroxy-naphthoquinone lapachol arrests mycobacterial growth and immunomodulates host macrophages.

The present study reports the anti-mycobacterial activity of 2-hydroxy-3-(3-methyl-2-butenyl)-1,4-naphthoquinone (lapachol) as well as its influence on macrophage functions. Lapachol (L) did not induce apoptosis/necrosis of THP-1 macrophages at ≤32 µg/mL. Mycobacterium avium liquid growth was arrested by ≥32 µg/mL and intra-macrophage proliferation by ≥16 µg/mL lapachol. The main immuno-modulatory effects of lapachol observed were an up-regulation of interferon-γ-receptor 1 (IFN-γR1) and major histocompatibility complex class II (MHCII) surface expression, and a marked inhibition of IL-10 secretion. Lapachol did not affect resting, IFN-γ- or toll-like receptor 2 (TLR2)-induced levels of oxygen and nitrogen metabolism key proteins nor the TLR2-mediated secretion of TNF-α, nor induced either oxidative or endoplasmic reticulum (ER) stress. Lapachol inhibited the surface expression of the co-stimulatory molecule CD86 but not that of CD80 and CD83. The results obtained indicate that the substituted naphthoquinone lapachol exhibits an anti-mycobacterial activity that is more efficient intra- than extra-cellularly, and exerts immuno-modulatory effects some of which may enhance the capacity of the host cell to control mycobacterial growth. The immune-modulatory action of lapachol could contribute to its more efficient intra-macrophage anti-mycobacterial activity.