Cytokine storms in infectious diseases.

The term “cytokine storm” has been adopted in the past several decades as a phrase to describe the aberrant production of soluble mediators and the accompanying immunopathology that ensues following severe viral and bacterial infections. However, “cytokine storm” was initially coined in the early 1990s to characterize the pathological condition that accompanied organ transplantation, an allogenic response to foreign tissue called graft vs host disease [1, 2]. More recently, aberrant immune responses and cytokine production have been associated with the pathogenesis of multiple disease states ranging from viral infection to neurological disorders [3]. Despite a definitive link of cytokine and chemokine levels with morbidity and mortality following infectious insults, no effective therapeutic treatments or modalities have been developed to quell the pathology associated with cytokine storm. In fact, the apparent intractability of tested therapies to subdue pathology has led some to postulate whether robust cytokine and chemokine production observed during these disease states is directly causal to the clinical manifestations. One major reason for this is that the kinetics, cellular sources, and cytokine milieu that mediate disease pathology remain poorly understood. This special issue of Seminars in Immunopathology entitled “Cytokine Storms in Infectious Diseases” focuses on the role of cytokines and other soluble mediators and their function in promoting pathology during infectious diseases and highlights emerging data that may point the way toward novel therapeutic interventions.

The immune system secretes soluble mediators to instruct both innate and adaptive immune responses to respond appropriately to infectious insults. Thus, cytokines and chemokines play a vital role in maintaining a healthy state through efficient control of invading microbes. Clark and Vissel review the history of cytokine storm and highlight the roles cytokines play in instructing proper immune responses as well as mediating determinantal immunopathology [4]. The primary focus is on the role of two historical soluble mediators, Tumor necrosis factor-α (TNF-α) and Interleuken-1 (IL-1), in multiple acute and chronic disease states. Moreover, the authors review the role non-resolving persistent inflammation plays in neurodegenerative disease states. Finally, the authors emphasize that understanding how the varying degrees of acuteness and chronicity of cytokine storms influence various diseases will be crucial in developing novel therapies to control associated pathologies.

The link between inflammatory cytokine/chemokine production and clinical disease following sepsis in patients has been recognized for several decades [5, 6]. Despite this strong correlation, no effective therapies targeting the inflammatory response have been generated to alleviate sepsis associated morbidity and mortality. Chousterman et al. review the contribution of various cytokines to the pathophysiology of sepsis [7]. Importantly, the authors emphasize that the kinetics of cytokine production following sepsis is likely to dictate successful therapeutic intervention. Moreover, they stress that patient sub-setting will be crucial for administering effective therapies to diverse patient populations. Finally, the authors underscore the importance of increased vascular permeability following sepsis and highlight treatments that target endothelial cell function as potential therapeutic options for a subset of sepsis patients.

Respiratory viral infections

Elevated cytokine and chemokine production has been continuously associated with poor clinical outcome and pathogenesis during respiratory viral infections in humans and animal models [8-10]. Perlman and Thomas et al. review in detail the role various cytokines, chemokines and innate immune cells play in promoting pathology or protection during two clinically important respiratory viruses: coronaviruses (CoV) and influenza viruses, respectively [11, 12]. Specifically, Channappanavar and Perlman highlight how pathogenic CoV antagonize early type 1 interferon signaling which promotes rapid virus replication, setting the stage for an exacerbated secondary inflammatory environment marked by elevated cytokines/chemokines and accumulation of inflammatory monocytes/macrophages and neutrophils in the infected lung [11]. Moreover, Guo and Thomas emphasize the emerging roles of type 2 cytokines such as amphiregulin in dampening inflammation and promoting tissue repair [12]. Both reviews discuss the current experimental anti-inflammatory strategies being tested in vivo in animal models including Sphingosine 1 phosphate modulators, COX inhibitors, PPAR (peroxisome proliferator-activated receptor) agonists and modulation of production/signaling of oxidized phospholipids, and their potential as future therapeutic options to ameliorate cytokine storm pathology during respiratory viral infection.

Pathogenesis of viral hemorrhagic fevers

The recent deadly outbreak of Ebola virus in West Africa which killed over 11,000 people sparked fear into millions of people in the USA when the virus made its way to America. While Ebola virus pathology is the result of multiple factors, excessive inflammatory responses are a significant feature following infection. Probably the most notable symptom is hemorrhage which can occur at varying degrees of severity following Ebola virus infection. The aberrant inflammatory response that accompanies Ebola virus infection, termed viral hemorrhagic fever (VHF), can be caused by multiple RNA viruses, including arenaviruses, bunyaviruses, filoviruses, and flaviviruses. Basler reviews the linkages between excessive inflammatory responses, hemorrhage and disseminated intravascular coagulation in the pathological manifestation of VHF in humans and non-human primates [13]. The review highlights potential sources of inflammatory cytokines during multiple VHF infections and points out that while dendritic cells are targets of viral replication by multiple VHF viruses, these cells secrete minimal amounts of cytokines/chemokines while monocytes and macrophages appear to be significant sources of inflammatory cytokines during these infections. The author highlights that the most relevant cell types and signaling pathways responsible for disease pathology in vivo have yet to be determined and understanding how the cytokine storm progresses in vivo will likely yield optimal therapeutics to subdue pathology associated with these infections.

Role of cytokine storm in dengue virus pathogenesis

Dengue virus infection and disease is endemic to the tropical and sub-tropical regions of the globe, largely due to the vector borne nature of its infection cycle where primary mosquito infection is necessary for transmission to humans. However, the recent warming of the globe has begun to push mosquitos that transmit dengue further north, making parts of the USA and southern European nations more likely to experience dengue infection. Although severe dengue infection occurs in a minority of patients, the accompanying dengue hemorrhagic fever (DHF) is characterized by increased vascular permeability, hemorrhage, and organ failure. In this series, Rothman and colleagues review how both innate and adaptive immune responses contribute to promoting the severe manifestation of DHF [14]. The authors also review specific key cytokines and chemokines, namely TNF-α, vascular endothelial growth factors (VEGF-A), IL-6, IL-10, IL-8, CCL2, and CXCL10, and how their production promotes clinical presentation of DHF. However, the authors point out that efficacious therapies for DHF will likely require targeting proteins that suppress multiple inflammatory pathways in humans. Thus, due to the absence of good animal models, there is an urgent need for well-designed patient studies coupled to competent bioinformatic analysis to identify reliable factors and pathways that promote DHF pathology.

Strategies to mitigate cytokine storm and future perspectives

Current research is illuminating the cellular and molecular contributors of cytokine storm in multiple disease states. Based on recent developments in the field, new therapies will likely move away from targeting single soluble mediators and focus more generally on inflammatory cascades. However, what signaling cascades are targeted will depend both on the infection as well as the targeted patient population. Current experimental anti-inflammatory strategies being tested in animal models include sphingosine 1 phosphate modulators [15, 16], COX inhibitors, Slit-Robo4 pathway modulators [17], PAR2 agonists [18], modulation of production/signaling of oxidized phospholipids [19], and TLR4 antagonists [20]. However, it is clear from ongoing studies that global blunting, not ablation, of inflammatory mediators will likely be required to ameliorate pathology associated with cytokine storm as one must balance suppression of immune pathology with proper control of the infectious agent.