Viral haemorrhagic septicaemia (VHS) outbreaks in Finnish rainbow trout farms

In Finland, viral haemorrhagic septicaemia virus (VHSV) was diagnosed for the first time in 2000 from 4 rainbow trout farms in brackish water. Since then the infection has spread and, by the end of 2004, VHSV had been isolated from 24 farms in 3 separate locations: 2 in the Baltic Sea and 1 in the Gulf of Finland. The pathogenicity of 3 of these isolates from 2 separate locations was analysed in infection experiments with rainbow trout fry. The cumulative mortalities induced by waterborne and intraperitoneal challenge were approximately 40 and 90 %, respectively. Pair-wise comparisons of the G and NV gene regions of Finnish VHSV isolates collected between 2000 and 2004 revealed that all isolates were closely related, with 99.3 to 100% nucleotide identity, which suggests the same origin of infection. Phylogenetic analysis revealed that they were closely related to the old freshwater isolates from rainbow trout in Denmark and to one old marine isolate from cod in the Baltic Sea, and that they were located close to the presumed ancestral source. As the Finnish isolates induce lower mortality than freshwater VHSV isolates in infection experiments, they could represent an intermediate stage of marine isolates evolving towards pathogenicity in rainbow trout.     

Viral vectors as potential HIV-1 vaccines

Vaccine vectors based on recombinant viruses have great promise to play an important role in the development of an effective HIV-1 vaccine. Within the last 10 years a wide range of viruses have been investigated for their ability to express protein(s) from foreign pathogens and to induce specific immunological responses against these antigen(s) in vivo. Each viral vector has its own unique biological characteristics and thus far none of them has proven to be an ideal candidate as a vaccine vehicle for HIV-1. This review focuses on both replication competent and non-replication competent viral vectors as a potential HIV-1 vaccine. Other approaches for the development of an HIV-1 vaccine are reviewed elsewhere and are beyond the scope of this review.     

The role and therapeutic potential of heat shock proteins in haemorrhagic stroke

Heat shock proteins (HSPs) are induced after haemorrhagic stroke, which includes subarachnoid haemorrhage (SAH) and intracerebral haemorrhage (ICH). Most of these proteins function as neuroprotective molecules to protect cerebral neurons from haemorrhagic stroke and as markers to indicate cellular stress or damage. The most widely studied HSPs in SAH are HSP70, haeme oxygenase‐1 (HO‐1), HSP20 and HSP27. The subsequent pathophysiological changes following SAH can be divided into two stages: early brain injury and delayed cerebral ischaemia, both of which determine the outcome for patients. Because the mechanisms of HSPs in SAH are being revealed and experimental models in animals are continually maturing, new agents targeting HSPs with limited side effects have been suggested to provide therapeutic potential. For instance, some pharmaceutical agents can block neuronal apoptosis signals or dilate cerebral vessels by modulating HSPs. HO‐1 and HSP70 are also critical topics for ICH research, which can be attributed to their involvement in pathophysiological mechanisms and therapeutic potential. However, the process of HO‐1 metabolism can be toxic owing to iron overload and the activation of succedent pathways, for example, the Fenton reaction and oxidative damage; the overall effect of HO‐1 in SAH and ICH tends to be protective and harmful, respectively, given the different pathophysiological changes in these two types of haemorrhagic stroke. In the present study, we focus on the current understanding of the role and therapeutic potential of HSPs involved in haemorrhagic stroke. Therefore, HSPs may be potential therapeutic targets, and new agents targeting HSPs are warranted.     

Viral macrodomains: a structural and evolutionary assessment of the pharmacological potential

Viral macrodomains possess the ability to counteract host ADP-ribosylation, a post-translational modification implicated in the creation of an antiviral environment via immune response regulation. This brought them into focus as promising therapeutic targets, albeit the close homology to some of the human macrodomains raised concerns regarding potential cross-reactivity and adverse effects for the host. Here, we evaluate the structure and function of the macrodomain of SARS-CoV-2, the causative agent of COVID-19. We show that it can antagonize ADP-ribosylation by PARP14, a cellular (ADP-ribosyl)transferase necessary for the restriction of coronaviral infections. Furthermore, our structural studies together with ligand modelling revealed the structural basis for poly(ADP-ribose) binding and hydrolysis, an emerging new aspect of viral macrodomain biology. These new insights were used in an extensive evolutionary analysis aimed at evaluating the druggability of viral macrodomains not only from the Coronaviridae but also Togaviridae and Iridoviridae genera (causing diseases such as Chikungunya and infectious spleen and kidney necrosis virus disease, respectively). We found that they contain conserved features, distinct from their human counterparts, which may be exploited during drug design.     

Real time bayesian estimation of the epidemic potential of emerging infectious diseases

Background

Fast changes in human demographics worldwide, coupled with increased mobility, and modified land uses make the threat of emerging infectious diseases increasingly important. Currently there is worldwide alert for H5N1 avian influenza becoming as transmissible in humans as seasonal influenza, and potentially causing a pandemic of unprecedented proportions. Here we show how epidemiological surveillance data for emerging infectious diseases can be interpreted in real time to assess changes in transmissibility with quantified uncertainty, and to perform running time predictions of new cases and guide logistics allocations.

Methodology/Principal Findings

We develop an extension of standard epidemiological models, appropriate for emerging infectious diseases, that describes the probabilistic progression of case numbers due to the concurrent effects of (incipient) human transmission and multiple introductions from a reservoir. The model is cast in terms of surveillance observables and immediately suggests a simple graphical estimation procedure for the effective reproductive number R (mean number of cases generated by an infectious individual) of standard epidemics. For emerging infectious diseases, which typically show large relative case number fluctuations over time, we develop a Bayesian scheme for real time estimation of the probability distribution of the effective reproduction number and show how to use such inferences to formulate significance tests on future epidemiological observations.

Conclusions/Significance

Violations of these significance tests define statistical anomalies that may signal changes in the epidemiology of emerging diseases and should trigger further field investigation. We apply the methodology to case data from World Health Organization reports to place bounds on the current transmissibility of H5N1 influenza in humans and establish a statistical basis for monitoring its evolution in real time.     

Assessing potential countermeasures against the dengue epidemic in non-tropical urban cities

Background

Dengue is a common mosquito-borne viral disease epidemic especially in tropical and sub-tropical regions where water sanitation is not substantially controlled. However, dengue epidemics sometimes occur in non-tropical urban cities with substantial water sanitary control. Using a mathematical model, we investigate what conditions can be important for a dengue epidemic to occur in an urban city such as Tokyo, where vectors are active only in summer and there are little number of vectors around hosts.

Methods

The model, which is a modified Ross-Macdonald model, consists of two sets of host-vector compartments. The two sets correspond to high-risk and low-risk areas, and only hosts can move between them. Assuming that mosquitoes have constant activity for only 90 days, we assess five potential countermeasures: (1) restricted movement between the two areas, (2) insecticide application, (3) use of repellents, (4) vector control, and (5) isolation of the infected.

Results

The basic reproduction number R ₀ and the cumulative number of infected hosts for 90 days are evaluated for each of the five countermeasures. In the cases of Measures 2–5, the cumulative number of the infected for 90 days can be reduced substantially for small R ₀ even if R ₀>1. Although R ₀ for Measure 1 monotonically decreases with the mobility rates, the cumulative number of the infected for 90 days has a maximum at a moderate mobility rate. If the mobility rate is sufficiently small, the restricted movement effectively increases the number density of vectors in the high-risk area, and the epidemic starts earlier in the high-risk area than in the low-risk one, while the growth of infections is slow.

Conclusions

Measures 2–5 are more or less effective. However, Measure 1 can have the opposite effect, depending on the mobility rates. The restricted movement results in the formation of a kind of core population, which can promote the epidemic in the entire population.

     

Viral load of various tissues of rainbow trout challenged with viral haemorrhagic septicaemia virus at various stages of disease

Market-sized rainbow trout Oncorhynchus mykiss were challenged by waterborne exposure to viral haemorrhagic septicaemia virus (VHSV isolate of genogroup Ia). Fish were sampled at 4 stages of infection (before onset of clinical signs, clinically affected fish, mortalities and survivors) and the viral load determined in (1) internal organs, (2) muscle tissue and (3) brain and gill tissue. Virus levels were determined by virus titration and real-time RT-PCR. VHSV was detected by either method in the majority of fish before onset of clinical signs and in the survivor group as well as in all fish in the clinically affected fish and mortality groups. Mean virus amounts per mg of tissue determined by virus titration (TCID50) or real-time RT-PCR (copy number) were > 10(4) in preclinical fish, > 10(3.8) in clinically affected fish, > 10(3.9) in mortalities and > 10(1.2) in survivors. Virus levels tended to be highest in the internal organs of subclinical and clinically affected fish and in brain and gill tissue of survivors. The results demonstrate that significant levels of VHSV can be found in tissues of rainbow trout that may be marketed for human consumption, which may have relevance for the biosecurity of VHS-free areas.     

Past and future epidemic potential of chikungunya virus in Australia

BackgroundAustralia is theoretically at risk of epidemic chikungunya virus (CHIKV) activity as the principal vectors are present on the mainland Aedes aegypti) and some islands of the Torres Strait (Ae. aegypti and Ae. albopictus). Both vectors are highly invasive and adapted to urban environments with a capacity to expand their distributions into south-east Queensland and other states in Australia. We sought to estimate the epidemic potential of CHIKV, which is not currently endemic in Australia, by considering exclusively transmission by the established vector in Australia, Ae. aegypti, due to the historical relevance and anthropophilic nature of the vector.Methodology/Principal findingsWe estimated the historical (1995–2019) epidemic potential of CHIKV in eleven Australian locations, including the Torres Strait, using a basic reproduction number equation. We found that the main urban centres of Northern Australia could sustain an epidemic of CHIKV. We then estimated future trends in epidemic potential for the main centres for the years 2020 to 2029. We also conducted uncertainty and sensitivity analyses on the variables comprising the basic reproduction number and found high sensitivity to mosquito population size, human population size, impact of vector control and human infectious period.Conclusions/SignificanceBy estimating the epidemic potential for CHIKV transmission on mainland Australia and the Torres Strait, we identified key areas of focus for controlling vector populations and reducing human exposure. As the epidemic potential of the virus is estimated to rise towards 2029, a greater focus on control and prevention measures should be implemented in at-risk locations.     

Endemic infection reduces transmission potential of an epidemic parasite during co-infection

Endemic, low-virulence parasitic infections are common in nature. Such infections may deplete host resources, which in turn could affect the reproduction of other parasites during co-infection. We aimed to determine whether the reproduction, and therefore transmission potential, of an epidemic parasite was limited by energy costs imposed on the host by an endemic infection. Total lipids, triacylglycerols (TAG) and polar lipids were measured in cockroaches (Blattella germanica) that were fed ad libitum, starved or infected with an endemic parasite, Gregarina blattarum. Reproductive output of an epidemic parasite, Steinernema carpocapsae, was then assessed by counting the number of infective stages emerging from these three host groups. We found both starvation and gregarine infection reduced cockroach lipids, mainly through depletion of TAG. Further, both starvation and G. blattarum infection resulted in reduced emergence of nematode transmission stages. This is, to our knowledge, the first study to demonstrate directly that host resource depletion caused by endemic infection could affect epidemic disease transmission. In view of the ubiquity of endemic infections in nature, future studies of epidemic transmission should take greater account of endemic co-infections.     

A single mutation in chikungunya virus affects vector specificity and epidemic potential

Chikungunya virus (CHIKV) is an emerging arbovirus associated with several recent large-scale epidemics. The 2005-2006 epidemic on Reunion island that resulted in approximately 266,000 human cases was associated with a strain of CHIKV with a mutation in the envelope protein gene (E1-A226V). To test the hypothesis that this mutation in the epidemic CHIKV (strain LR2006 OPY1) might influence fitness for different vector species, viral infectivity, dissemination, and transmission of CHIKV were compared in Aedes albopictus, the species implicated in the epidemic, and the recognized vector Ae. aegypti. Using viral infectious clones of the Reunion strain and a West African strain of CHIKV, into which either the E1-226 A or V mutation was engineered, we demonstrated that the E1-A226V mutation was directly responsible for a significant increase in CHIKV infectivity for Ae. albopictus, and led to more efficient viral dissemination into mosquito secondary organs and transmission to suckling mice. This mutation caused a marginal decrease in CHIKV Ae. aegypti midgut infectivity, had no effect on viral dissemination, and was associated with a slight increase in transmission by Ae. aegypti to suckling mice in competition experiments. The effect of the E1-A226V mutation on cholesterol dependence of CHIKV was also analyzed, revealing an association between cholesterol dependence and increased fitness of CHIKV in Ae. albopictus. Our observation that a single amino acid substitution can influence vector specificity provides a plausible explanation of how this mutant virus caused an epidemic in a region lacking the typical vector. This has important implications with respect to how viruses may establish a transmission cycle when introduced into a new area. Due to the widespread distribution of Ae. albopictus, this mutation increases the potential for CHIKV to permanently extend its range into Europe and the Americas.