Therapeutic opportunities in dengue infection

Abstract

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. Key words: Dengue; therapeutics; animal models; inflammation; antiviral DENGUE: OVERVIEWDengue is caused by a lipid-enveloped virus that contains a single-stranded, positive-sense RNA genome, the Dengue virus (DENV), which exists as four closely related serotypes (DENV-1-4). Dengue virus is a member of the Flaviviridae family and is related to the viruses that cause yellow fever and the Japanese, St. Louis, and West Nile encephalitides. As with other Flaviviruses, they are introduced into the host by an infected vector, Aedes aegypti and A. albopictus DDRPublished online in Wiley Online Library (wileyonlinelibrary.com).

A Model of DENV-3 Infection That Recapitulates Severe Disease and Highlights the Importance of IFN-γ in Host Resistance to Infection

“…Several studies in mice and humans have noted higher levels of viremia in severe dengue disease, which supports the assertion that increased viral replication is associated with more severe disease manifestation [17]–[21]. However, we and other groups have also demonstrated that inflammatory response, characterized by cytokine storm, also plays a fundamental role in dengue pathogenesis [7], [22]–[29]. Most of these studies were first characterized in a model of dengue infection using a mouse-adapted DENV-2 strain that mimics several clinical parameters seen in human disease, without affecting the CNS [22], [24]–[28].…”

Administration of plasmacytoid dendritic cell-stimulative lactic acid bacteria is effective against dengue virus infection in mice

“…At present, however, there are few preventative antiviral drugs or vaccines against dENV infection. Therefore, effective therapeutics and/or prophylaxis against dENV infection are urgently required (8).…”

Subversion of early innate antiviral responses during antibody-dependent enhancement of Dengue virus infection induces severe disease in immunocompetent mice

“…It is defined as an acute systemic viral infection transmitted to humans by Aedes mosquitoes, with a wide spectrum of clinical presentations, varying from an asymptomatic or a self-limited illness, called dengue fever (DF), to the potentially lethal forms, dengue hemorrhagic fever and dengue shock syndrome (DHF/Dss) [1][2][3]. Bhatt and colleagues showed using updated cartographic approaches that there are approximately 390 million dengue infectious cases per year around the world, of which 96 million manifest some level of disease severity [4].…”

“…the pathogenesis of Denv infection remains poorly understood and involves a complex interplay between viral and host factors [1,2,8]. severe forms of disease can be seen during primary infections [9,10]; however, epidemiological and observational studies demonstrate that the majority of DHF/Dss cases occur predominantly in either individuals with secondary heterologous Denv infections or in infants born from Denv-immune mothers [5,[11][12][13][14].…”

“…altogether, these findings show that there is suppression of early antiviral innate responses during antibody-mediated Denv infection, resulting in excessive virus replication and severe disease manifestation. specific therapeutic options for severe thrombocytopenia and shock syndrome, the main causes of mortality during severe dengue disease, are still lacking [1,42]. the aDe phenomenon is considered a major bottleneck during the vaccine design and antibody therapeutic approaches development [15,61,62].…”