Host-cell sensors for Plasmodium activate innate immunity against liver-stage infection

Pasieka

et al. 2016

J Virol

The interferon (IFN) response to viral pathogens is critical for host survival. In humans and mouse models, defects in IFN responses can result in lethal herpes simplex virus 1 (HSV-1) infections, usually from encephalitis. Although rare, HSV-1 can also cause fulminant hepatic failure, which is often fatal. Although herpes simplex encephalitis has been extensively studied, HSV-1 generalized infections and subsequent acute liver failure are less well understood. We previously demonstrated that IFN- IMPORTANCEHerpes simplex virus 1 (HSV-1) infection is an incurable viral infection with the most significant morbidity and mortality occurring in neonates and patients with compromised immune systems. Severe pathologies from HSV include the blindness-inducing herpetic stromal keratitis, highly debilitating and lethal herpes simplex encephalitis, and generalized infections that can lead to herpes simplex virus-induced acute liver failure. While immune compromise is a known factor, the precise mechanisms that lead to generalized HSV infections are unknown. In this study, we used and developed a mouse model system in combination with real-time bioluminescence imaging to demonstrate the relative importance of the immune and nonimmune compartments for containing viral spread and promoting host survival after corneal infection. Our results shed light on the pathogenesis of HSV infections that lead to generalized infection and acute liver failure. Herpes simplex virus 1 (HSV-1) is an enveloped DNA virus and a member of the Alphaherpesvirus subfamily with high seroprevalence in the human population (1). In most cases, HSV-1 causes relatively mild orolabial cold sores, but it can cause more serious localized diseases such herpes stromal keratitis, the leading cause of infectious blindness in the United States (2, 3). Serious sequelae for HSV-1 are more common in immunocompromised hosts and neonates, with uncontrolled viral replication leading to herpes simplex encephalitis (HSE) or, more rarely, HSV sepsis leading to acute liver failure (4, 5). HSV-induced acute liver failure (ALF) is an alarmingly deadly disease with a lethality rate approaching 75% (5). The importance of studying HSV-induced ALF is underscored by the immunocompromised populations it affects, mainly patients undergoing chemotherapy, bone marrow transplant recipients, HIV patients, and women in the third trimester of pregnancy (5, 6). HSV-1 infects via the mucosae of the mouth, eyes, or genitalia, where it undergoes lytic replication in the epithelium (7). During infection of these mucosae, the virus infects innervating sensory neurons, traveling in a retrograde direction in the facial neurons back to mostly sensory ganglia, wherein HSV-1 establishes latency (8). The ability of HSV to establish latency in neurons, a nondividing cell population, hinders the ability of the immune system to fully clear the virus and renders the virus refractory to cure with antiviral treatments (9). Immune dysregulation and other stimuli cause HSV-1 to erupt from latency,...

Section: Discussionsupporting

confidence: 74%

Immune- and Nonimmune-Compartment-Specific Interferon Responses Are Critical Determinants of Herpes Simplex Virus-Induced Generalized Infections and Acute Liver Failure

Pasieka

et al. 2016

J Virol

The Journal of Immunology

“…In addition to TLR7/TLR9-dependent mechanisms (160,161), type I IFNs can be induced in a STING, TBK1, IRF3/IRF7-dependent manner via AT-rich stem-loop DNA (162). P. berghei-derived RNA also can trigger IFN-b production in a melanoma differentiation-associated protein 5/MAVS-dependent manner (163). However, it is unknown how these pathogen products gain access to the cytosol.…”

Section: Plasmodiummentioning

confidence: 99%

“…Type I IFNs were shown to mediate protection against blood-stage (164) and liver-stage (163,165) malaria in infected animals. However, recent studies revealed that type I IFNs increase host susceptibility to cerebral malaria (162,166).…”

Section: Plasmodiummentioning

confidence: 99%

Interfering with Immunity: Detrimental Role of Type I IFNs during Infection

Stifter¹,

Feng²

2015

Type I IFNs are known to inhibit viral replication and mediate protection against viral infection. However, recent studies revealed that these cytokines play a broader and more fundamental role in host responses to infections beyond their well-established antiviral function. Type I IFN induction, often associated with microbial evasion mechanisms unique to virulent microorganisms, is now shown to increase host susceptibility to a diverse range of pathogens, including some viruses. This article presents an overview of the role of type I IFNs in infections with bacterial, fungal, parasitic, and viral pathogens and discusses the key mechanisms mediating the regulatory function of type I IFNs in pathogen clearance and tissue inflammation.

“…This second-generation GAP3KO showed a much better safety profile in more stringent preclinical tests [26], and has recently completed successful Phase I safety trials in humans in which it appears safe and immunogenic [ In addition to the development of novel vaccine strategies, the access to liver stages afforded by rodent models allows for the interrogation of innate immune responses. Once thought to be immunologically inert, the liver stages of the parasite have recently been found to indeed induce innate immune responses that are capable of limiting parasite growth [27][28][29]. How exactly the parasite is sensed is still under investigation [30], and it is also unknown how these early innate events could influence the ensuing adaptive response.…”

Section: Lessons Learned From Rodent Malaria Modelsmentioning

confidence: 99%

“…Once thought to be immunologically inert, the liver stages of the parasite have recently been found to indeed induce innate immune responses that are capable of limiting parasite growth [27][28][29]. How exactly the parasite is sensed is still under investigation [30], and it is also unknown how these early innate events could influence the ensuing adaptive response.…”

mentioning

confidence: 99%

An Expanding Toolkit for Preclinical Pre-Erythrocytic Malaria Vaccine Development: Bridging Traditional Mouse Malaria Models and Human Trials

2016

Malaria remains a significant public health burden with 214 million new infections and over 400,000 deaths in 2015. Elucidating relevant Plasmodium parasite biology can lead to the identification of novel ways to control and ultimately eliminate the parasite within geographic areas. Particularly, the development of an effective vaccine that targets the clinically silent pre-erythrocytic stages of infection would significantly augment existing malaria elimination tools by preventing both the onset of blood-stage infection/disease as well as spread of the parasite through mosquito transmission. In this Perspective, we discuss the role of small animal models in pre-erythrocytic stage vaccine development, highlighting how human liver-chimeric and human immune system mice are emerging as valuable components of these efforts. Malaria continues to cause significant morbidity and mortality despite renewed and concerted efforts to eliminate the causative agents, parasites of the genus Plasmodium. These efforts have largely focused on control of the Anopheles mosquito vectors, and antimalarial drug treatment of symptomatic infected individuals. The 214 million new malaria infections and 438,000 deaths due to malaria in 2015 were disproportionately borne by low income countries where malaria is endemic, and declines in malaria infections since 2000 have been slowest in countries with low resource availability and high malaria burden [1]. In the fight against malaria, effective vaccines preventing both disease and transmission will be important tools to achieve WHO goals of a 90% reduction in disease burden by 2030 [1,2]. In humans, malaria is caused predominantly by the parasite species Plasmodium falciparum and Plasmodium vivax, with the remainder of infections caused by three additional parasite species, Plasmodium malariae, Plasmodium ovale and Plasmodium knowlesi [1].Malaria parasite transmission occurs when a Plasmodium-infected Anopheles mosquito bites and by probing the skin for a blood meal, deposits motile sporozoite stages into the host. Sporozoites pass through the dermis using active motility, enter a capillary and then rapidly home to the liver. Once in the liver sporozoites enter the parenchyma and infect hepatocytes, wherein they then transmogrify into liver stages, which grow, replicate and ultimately differentiate into tens of thousands of first-generation merozoites. Merozoites of human malaria parasites emerge from the liver into the blood stream 7-10 days after transmission, where they undergo cyclic erythrocytic infection and intraerythrocytic replication. This blood-stage infection is responsible for all mortality and clinical symptoms of malaria, as well as infection of a new mosquito vector by sexual stage parasites for onward transmission [3,4]. Stages prior to blood-stage infection (i.e., the sporozoite and liver stages) are collectively known as preerythrocytic (PE) stages of infection and vaccine candidates targeting these stages are collectively termed PE vaccines. By preventing progression to ...