The Hepatitis E Virus Open Reading Frame 2 Protein: Beyond Viral Capsid

Hepatitis E virus (HEV) is a zoonotic pathogen causing hepatitis in both human and animal hosts, which is responsible for acute hepatitis E outbreaks worldwide. The 7.2 kb genome of the HEV encodes three well-defined open reading frames (ORFs), where the ORF2 translation product acts as the major virion component to form the viral capsid. In recent years, besides forming the capsid, more functions have been revealed for the HEV-ORF2 protein, and it appears that HEV-ORF2 plays multiple functions in both viral replication and pathogenesis. In this review, we systematically summarize the recent research advances regarding the function of the HEV-ORF2 protein such as application in the development of a vaccine, regulation of the innate immune response and cellular signaling, involvement in host tropism and participation in HEV pathogenesis as a novel secretory factor. Progress in understanding more of the function of HEV-ORF2 protein beyond the capsid protein would contribute to improved control and treatment of HEV infection.

Bactericidal activity of avian complement: a contribution to understand avian-host tropism of Lyme borreliae

Complement has been considered as an important factor impacting the host–pathogen association of spirochetes belonging to the Borrelia burgdorferi sensu lato complex, and may play a role in the spirochete’s ecology. Birds are known to be important hosts for ticks and in the maintenance of borreliae. Recent field surveys and laboratory transmission studies indicated that certain avian species act as reservoir hosts for different Borrelia species. Nevertheless, our current understanding of the molecular mechanisms determining host tropism of Borrelia is still in its fledgling stage. Concerning the role of complement in avian-host tropism, only a few bird species and Borrelia species have been analysed so far. Here, we performed in vitro serum bactericidal assays with serum samples collected from four bird species including the European robin Erithacus rubecula, the great tit Parus major, the Eurasian blackbird Turdus merula, and the racing pigeon Columba livia, as well as four Borrelia species (B. afzelii, B. garinii, B. valaisiana, and B. burgdorferi sensu stricto). From July to September 2019, juvenile wild birds were caught using mist nets in Portugal. Racing pigeons were sampled in a loft in October 2019. Independent of the bird species analysed, all Borrelia species displayed an intermediate serum-resistant or serum-resistant phenotype except for B. afzelii challenged with serum from blackbirds. This genospecies was efficiently killed by avian complement, suggesting that blackbirds served as dead-end hosts for B. afzelii. In summary, these findings suggest that complement contributes in the avian–spirochete–tick infection cycle and in Borrelia-host tropism.

Characterization of SARS-CoV-2 variants B.1.617.1 (Kappa), B.1.617.2 (Delta) and B.1.618 on cell entry, host range, and sensitivity to convalescent plasma and ACE2 decoy receptor

ABSTRACTRecently, highly transmissible SARS-CoV-2 variants B.1.617.1 (Kappa), B.1.617.2 (Delta) and B.1.618 were identified in India with mutations within the spike proteins. The spike protein of Kappa contains four mutations E154K, L452R, E484Q and P681R, and Delta contains L452R, T478K and P681R, while B.1.618 spike harbors mutations Δ145-146 and E484K. However, it remains unknown whether these variants have altered in their entry efficiency, host tropism, and sensitivity to neutralizing antibodies as well as entry inhibitors. In this study, we found that Kappa, Delta or B.1.618 spike uses human ACE2 with no or slightly increased efficiency, while gains a significantly increased binding affinity with mouse, marmoset and koala ACE2 orthologs, which exhibits limited binding with WT spike. Furthermore, the P618R mutation leads to enhanced spike cleavage, which could facilitate viral entry. In addition, Kappa, Delta and B.1.618 exhibits a reduced sensitivity to neutralization by convalescent sera owning to the mutation of E484Q, T478K, Δ145-146 or E484K, but remains sensitive to entry inhibitors-ACE2-lg decoy receptor. Collectively, our study revealed that enhanced human and mouse ACE2 receptor engagement, increased spike cleavage and reduced sensitivity to neutralization antibodies of Kappa, Delta and B.1.618 may contribute to the rapid spread of these variants and expanded host range. Furthermore, our result also highlighted that ACE2-lg could be developed as broad-spectrum antiviral strategy against SARS-CoV-2 variants.

Gain of Function Research: the Clairvoyant Lens on Pandemics

Pandemic influenza viruses have emerged three times in this century. It is important to examine the potential risk of novel microorganisms/viruses through the add-on research mechanism of Gain of Function Research (GoFR). This mechanism consists of the practice of serial passaging of microorganisms to increase their transmissibility, virulence, immunogenicity, and host tropism through the inclusive feature of selective pressure of culture medium. Although, the GoFR can be a double-edged sword that has the potential to give an insight and better appreciation of current and future pandemics with antecedent apprehension of initiating a pandemic, itself. Moreover, with its inherent potential to give a head start on a virus, GoFR has the potential to develop vaccines or therapeutics, before the virus emerges in its true virulent form. Likewise, the GoFR studies can be vital in research on antivirals and antimicrobial agents and can help inform the development of combination therapies. Passive immunotherapy, which often includes a combination of products, is particularly dependent on GoFR experiments for evaluating efficacy. GoFR if made use of meticulously and with caution could help Medical Sciences and Humankind tremendously.

Host tropism determination by convergent evolution of immunological evasion in the Lyme disease system

Pathogens possess the ability to adapt and survive in some host species but not in others–an ecological trait known as host tropism. Transmitted through ticks and carried mainly by mammals and birds, the Lyme disease (LD) bacterium is a well-suited model to study such tropism. Three main causative agents of LD, Borrelia burgdorferi, B. afzelii, and B. garinii, vary in host ranges through mechanisms eluding characterization. By feeding ticks infected with different Borrelia species, utilizing feeding chambers and live mice and quail, we found species-level differences in bacterial transmission. These differences localize on the tick blood meal, and specifically complement, a defense in vertebrate blood, and a polymorphic bacterial protein, CspA, which inactivates complement by binding to a host complement inhibitor, Factor H (FH). CspA selectively confers bacterial transmission to vertebrates that produce FH capable of allele-specific recognition. CspA is the only member of the Pfam54 gene family to exhibit host-specific FH-binding. Phylogenetic analyses revealed convergent evolution as the driver of such uniqueness, and that FH-binding likely emerged during the last glacial maximum. Our results identify a determinant of host tropism in Lyme disease infection, thus defining an evolutionary mechanism that shapes host-pathogen associations.

Structural Basis of Glycan Recognition of Rotavirus

Rotavirus (RV) is an important pathogen causing acute gastroenteritis in young humans and animals. Attachment to the host receptor is a crucial step for the virus infection. The recent advances in illustrating the interactions between RV and glycans promoted our understanding of the host range and epidemiology of RVs. VP8*, the distal region of the RV outer capsid spike protein VP4, played a critical role in the glycan recognition. Group A RVs were classified into different P genotypes based on the VP4 sequences and recognized glycans in a P genotype-dependent manner. Glycans including sialic acid, gangliosides, histo-blood group antigens (HBGAs), and mucin cores have been reported to interact with RV VP8*s. The glycan binding specificities of VP8*s of different RV genotypes have been studied. Here, we mainly discussed the structural basis for the interactions between RV VP8*s and glycans, which provided molecular insights into the receptor recognition and host tropism, offering new clues to the design of RV vaccine and anti-viral agents.

A single-cell atlas of Plasmodium falciparum transmission through the mosquito

Malaria parasites have a complex life cycle featuring diverse developmental strategies, each uniquely adapted to navigate specific host environments. Here we use single-cell transcriptomics to illuminate gene usage across the transmission cycle of the most virulent agent of human malaria - Plasmodium falciparum. We reveal developmental trajectories associated with the colonization of the mosquito midgut and salivary glands and elucidate the transcriptional signatures of each transmissible stage. Additionally, we identify both conserved and non-conserved gene usage between human and rodent parasites, which point to both essential mechanisms in malaria transmission and species-specific adaptations potentially linked to host tropism. Together, the data presented here, which are made freely available via an interactive website, provide a fine-grained atlas that enables intensive investigation of the P. falciparum transcriptional journey. As well as providing insights into gene function across the transmission cycle, the atlas opens the door for identification of drug and vaccine targets to stop malaria transmission and thereby prevent disease.

The Intertwined Life Histories and Transmission Ecologies of Plant, Arthropod, and Vertebrate Viruses

It remains poorly understood how the life history strategies and transmission ecologies of viruses of plants, arthropods, and vertebrates are interrelated. The present analysis hinges on the virus transmission success. Virus transmission reflects where in the host-body viruses are retained or replicating. Plants, arthropods, and vertebrates share a protective outer-layer, a circulatory system, and reproductive organs. The latter enables vertical virus transmission and associates with virus-host mutualism. Two broadly opposing virus life history strategies are considered. Acute viruses tend to be replicative and are swiftly transmitted to the next host. Instead, persistent viruses keep virus replicating costs and host damage to a minimum. The intertwined life histories and transmission ecologies are accordingly pieced together, based on the virus mono- or instead dual-host tropism, the location of virus retention or replication on or in the host-body, the presence of cyclical or mechanical transmission by arthropods, and of horizontal and vertical host-to-host transmission modes. It is shown that in the arthropod and in the vertebrate animal host, virus circulation in the hemocoel or blood circulation goes hand-in-hand with vertical transmission. Instead, plant phloem viruses do not transmit via seed. The latter is the rule for the plant-only viruses. The risk management implications are discussed in brief.

Pmp Repertoires Influence the Different Infectious Potential of Avian and Mammalian Chlamydia psittaci Strains

Chlamydia psittaci is the etiological agent of chlamydiosis in birds and can be transmitted to humans, causing severe systemic disease. C. psittaci infects a broad range of hosts; strains are isolated not only from birds but also from mammals, where they seem to have a reduced infectious and zoonotic potential. Comparative analysis of chlamydial genomes revealed the coding sequences of polymorphic membrane proteins (Pmps) to be highly variable regions. Pmps are characterized as adhesins in C. trachomatis and C. pneumoniae and are immunoreactive proteins in several Chlamydia species. Thus, Pmps are considered to be associated with tissue tropism and pathogenicity. C. psittaci harbors 21 Pmps. We hypothesize that the different infectious potential and host tropism of avian and mammalian C. psittaci strains is dependent on differences in their Pmp repertoires. In this study, we experimentally confirmed the different virulence of avian and mammalian strains, by testing the survival rate of infected embryonated eggs and chlamydiae dissemination in the embryos. Further, we investigated the possible involvement of Pmps in host tropism. Analysis of pmp sequences from 10 C. psittaci strains confirmed a high degree of variation, but no correlation with host tropism was identified. However, comparison of Pmp expression profiles from different strains showed that Pmps of the G group are the most variably expressed, also among avian and mammalian strains. To investigate their functions, selected Pmps were recombinantly produced from one avian and one mammalian representative strain and their adhesion abilities and relevance for the infection of C. psittaci strains in avian and mammalian cells were tested. For the first time, we identified Pmp22D, Pmp8G, and OmcB as relevant adhesins, essential during infection of C. psittaci strains in general. Moreover, we propose Pmp17G as a possible key player for host adaptation, as it could only bind to and influence the infection in avian cells, but it had no relevant impact towards infection in mammalian cells. These data support the hypothesis that distinct Pmp repertoires in combination with specific host factors may contribute to host tropism of C. psittaci strains.