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Development of inflammatory diseases, such as metabolic syndrome and cancer, is prevalent in individuals that encounter continuous disruption of their internal clock. Further, daily oscillations in susceptibility to infection as well as a multitude of other immunological processes have been described. Much progress has been made and various mechanisms have been proposed to explain circadian variations in immunity; yet much is still unknown. Understanding the crosstalk between the circadian and the immune systems will allow us to manipulate clock outputs to prevent and treat inflammatory diseases in individuals at risk. This review briefly summarizes current knowledge about circadian rhythms and their role in the immune system and highlights progress and challenges in chrono-immunological research.

Dengue virus (DENV), a mosquito-borne flavivirus, is a public health problem in many tropical countries. IL-22 and IL-17A are key cytokines in several infectious and inflammatory diseases. We have assessed the contribution of IL-22 and IL-17A in the pathogenesis of experimental dengue infection using a mouse-adapted DENV serotype 2 strain (P23085) that causes a disease that resembles severe dengue in humans. We show that IL-22 and IL-17A are produced upon DENV-2 infection in immune-competent mice. Infected IL-22(-/-) mice had increased lethality, neutrophil accumulation and pro-inflammatory cytokines in tissues, notably IL-17A. Viral load was increased in spleen and liver of infected IL-22(-/-) mice. There was also more severe liver injury, as seen by increased transaminases levels and tissue histopathology. γδ T cells and NK cells are sources of IL-17A and IL-22, respectively, in liver and spleen. We also show that DENV-infected HepG2 cells treated with rhIL-22 had reduced cell death and decreased IL-6 production. IL-17RA(-/-) mice were protected upon infection and IL-17A-neutralizing-Ab-treatment partially reversed the phenotype observed in IL-22(-/-) -infected mice. We suggest that disrupting the balance between IL-22 and IL-17A levels may represent an important strategy to reduce inflammation and tissue injury associated with severe dengue infection.

Summary: Mammals are subject to colonization by an astronomical number of mutualistic and commensal microorganisms on their environmental exposed surfaces. These mutualistic species build up a complex community, called the indigenous microbiota, which aid their hosts in several physiological activities. In this review, we show that the transition between a non-colonized and a colonized state is associated with modification on the pattern of host inflammatory and behavioral responsiveness. There is a shift from innate anti-inflammatory cytokine production to efficient release of proinflammatory mediators and rapid mobilization of leukocytes upon infection or other stimuli. In addition, host responses to hypernociceptive and stressful stimuli are modulated by indigenous microbiota, partly due to the altered pattern of innate and acquired immune responsiveness of the non-colonized host. These altered responses ultimately lead to significant alteration in host behavior to environmental threats. Therefore, host colonization by indigenous microbiota modifies the way the host perceives and reacts to environmental stimuli, improving resilience of the entire host–microorganism consortium to environmental stresses.

Infection by one of the four serotypes of the arthropod-borne dengue virus produces a spectrum of disease manifestations, ranging from asymptomatic to life-threatening Dengue hemorrhagic fever/Dengue shock syndrome (DHF/DSS). During the last several decades, dengue has spread its geographic distribution to become the most common arboviral infection of humans in the subtropical and tropical regions of the world. There is no specific treatment or vaccine approved for human use. This fact, associated with the large number of infected individuals and the lack of markers that indicate which patients will develop severe disease, place an enormous burden on health systems of affected countries. Many efforts have been made to elucidate several aspects of dengue disease, but the pathogenesis of disease is complex and remains unclear. The hallmark of severe dengue disease is a short-lived plasma leakage that is believed to be immune mediated. Understanding the mechanism(s) that underlie the pathogenesis of dengue is critical for the development of safe therapeutics to prevent DHF/DSS. In this review, we highlight potential therapeutic alternatives to treat dengue infection and outline strategies used to develop and research anti-dengue therapies, focusing on in vivo results obtained using the experimental animal models currently available. Within this context, we discuss the therapeutic potential of novel antiviral molecules, either targeting virus-encoded functions or the cellular functions needed for viral replication. In addition, we discuss studies using anti-inflammatory strategies aimed at reducing the exacerbated host response against infection and their potential as promising therapeutic alternatives in severe dengue disease. Drug Dev Res 72:480–500, 2011. © 2011 Wiley-Liss, Inc.

Dengue fever is an emerging viral disease transmitted by arthropods to humans in tropical countries. Dengue hemorrhagic fever (DHF) is escalating in frequency and mortality rates. Here we studied the involvement of macrophage migration inhibitory factor (MIF) in dengue virus (DENV) infection and its pathogenesis. Patients with DHF had elevated plasma concentrations of MIF. Both leukocytes from these patients and macrophages from healthy donors infected in vitro with DENV showed a substantial amount of MIF within lipid droplets. The secretion of MIF by macrophages and hepatocytes required a productive infection and occurred without an increase in gene transcription or cell death, thus indicating active secretion from preformed stocks. In vivo infection of wild-type and mif-deficient (Mif(-/-)) mice demonstrated a role of MIF in dengue pathogenesis. Clinical disease was less severe in Mif(-/-) mice, and they exhibited a significant delay in lethality, lower viremia, and lower viral load in the spleen than wild-type mice. This reduction in all parameters of severity on DENV infection in Mif(-/-) mice correlated with reduced proinflammatory cytokine concentrations. These results demonstrated the contribution of MIF to the pathogenesis of dengue and pointed to a possible beneficial role of neutralizing MIF as an adjunctive therapeutic approach to treat the severe forms of the disease.