Unveiling Monkeypox virus emergence: What unfolded in the aftermath of the COVID-19 threat?

The emergence of the monkeypox virus (MPXV) outbreak presents a formidable challenge to human health. Emerging evidence suggests that individuals with HIV have been disproportionately affected by MPXV, with adverse clinical outcomes and higher mortality rates. However, the shared molecular mechanisms underlying MPXV and HIV remain elusive. We identified differentially expressed genes (DEGs) from two public data sets, GSE219036 and GSE184320, and extracted common DEGs between MPXV and HIV. We further performed gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), protein-protein interactions (PPI), candidate drug assessment, and immune correlation of hub genes analysis. We validated the key biomarkers using multiple machine learning (ML) methods including random forest (RF), t-distributed stochastic neighbor embedding (tSNE), and uniform manifold approximation and projection (UMAP). A total of 59 common DEGs were identified between MPXV and HIV. Our functional analysis highlighted multiple pathways, including the ERK cascade, NF-κB signaling, and various immune responses, playing a collaborative role in the progression of both diseases. The PPI and gene co-expression networks were constructed, and five key genes with significant immune correlations were identified and validated by multiple ML models, including SPRED1, SPHK1, ATF3, AKT3, and AKT1S1. Our study emphasizes the common pathogenesis of HIV and MPXV and highlights the pivotal genes and shared pathways, providing new opportunities for evidence-based management strategies in HIV patients co-infected with MPXV.

The emergence of the human monkeypox virus (MPXV) and the lack of effective medications have necessitated the exploration of various strategies to combat its infection. This study employs a network-based approach to drug discovery, utilizing the BLASTn and phylogenetic analysis to compare the MPXV genome with those of 18 related orthopoxviruses, revealing over 75 % genomic similarity. Through a literature review, 160 human-host proteins linked to MPXV and its relatives were identified, leading to the construction of a human-host protein interactome. Analysis of this interactome highlighted 39 central hub proteins, which were then examined for potential drug targets. The process successfully revealed 15 targets already approved for use with medications. Additionally, the functional enrichment analysis provided insights into potential pathways and disorders connected with these targets. Four medications, namely Baricitinib, Infliximab, Adalimumab, and Etanercept, have been identified as potential candidates for repurposing to combat MPXV. In addition, the pharmacophore-based screening identified a molecule that is comparable to Baricitinib and has the potential to be effective against MPXV. The findings of the study suggest that ZINC22060520 is a promising medication for treating MPXV infection and proposes these medications as potential options for additional experimental and clinical assessment in the battle against MPXV.

Monkeypox is a viral zoonotic disease, often transmitted to humans from animals. While the whole world is haggling with the COVID-19 pandemic, the emergence of the monkeypox virus (MPXV) arose as a new challenge to mankind. Till date, numerous cases related to the MPXV have been reported in several countries across the globe, but, its momentary distribution in the current time has left everyone in fright with increasing mortality and limited clinically approved treatments. Therefore, it is of immense importance to develop a potent and highly effective vaccine capable of inducing desired immunogenic responses against the highly contagious MPXV. Herein, using various immunoinformatic and computational biology tools, we made an attempt to develop a multi-epitope vaccine construct against the MPXV which is antigenic, non-allergen and non-toxic in nature and capable of exhibiting immunogenic behavior. The sequence of vaccine construct was designed using the proposed 4 MHC-I, 3 MHC-II and 4 B-cell epitopes linked with suitable adjuvant and linkers. The modeled structure of the vaccine construct was used to assess its interaction with the Toll-like Receptor 4 (TLR4) using ClusPro and HADDOCK. All-atoms molecular dynamics simulation of the MPXV vaccine construct-TLR4 complex followed by a high level of gene expression of the construct within the bacterial system affirmed its stability along with induction of immunogenic response within the host cell. Altogether, our immunoinformatic approach aid in the development of a stable chimeric vaccine construct against MPXV and needs further experimental validation for its immunological relevance and usefulness as a vaccine candidate. Communicated by Ramaswamy H. Sarma

The emergence or reemergence of monkeypox (Mpox) and Ebola virus (EBOV) agents causing zoonotic diseases remains a huge threat to human health. Our study aimed at designing a multi-epitope vaccine (MEV) candidate to target both the Mpox and EBOV agents using immunoinformatics tools. Viral protein sequences were retrieved, and potential nonallergenic, nontoxic, and antigenic epitopes were obtained. Next, cytotoxic and helper T-cell (CTL and HTL, respectively) and B-cell (BCL) epitopes were predicted, and those potential epitopes were fused utilizing proper linkers. The in silico cloning and expression processes were implemented using Escherichia coli K12. The immune responses were prognosticated using the C-ImmSim server. The MEV construct (29.53kDa) included four BCL, two CTL, and four HTL epitopes and adjuvant. The MEV traits were pertinent in terms of antigenicity, non-allergenicity, nontoxicity, physicochemical characters, and stability. The MEV candidate was also highly expressed in E. coli K12. The strong affinity of MEV-TLR3 was confirmed using molecular docking and molecular dynamics simulation analyses. Immune simulation analyses unraveled durable activation and responses of cellular and humoral arms alongside innate immune responses. The designed MEV candidate demonstrated appropriate traits and was promising in the prediction of immune responses against both Mpox and EBOV agents. Further experimental assessments of the MEV are required to verify its efficacy.

The recent emergence of monkeypox virus (MPXV) in the UK and elsewhere is of urgent public health concern. Several aspects of MPXV epidemiology and pathogenesis, including its systemic spread and viraemia during acute infection, furthermore represent an important potential threat to the safety of blood transfusion and organ transplantation. Reported infections in the UK have been exponentially increasing over the last 2 months, with 1552 reported cases in the UK by 7th July 2022. This is likely to be considerable underestimate given current limitations in diagnostic capacity and clinical diagnoses hampered by its similar disease presentations to other causes of rash and genitourinary disease. While MPXV infections are currently most widespread in gay, bisexual or other men who have sex with men, wider spread of MPXV outside defined risk groups for infection may prevent identification of infection risk in donors. While typically mild disease outcomes have been reported in UK cases, case fatality rates ranging from 1% to over 10% are reported for different MPXV strains in its source area in sub‐Saharan Africa. Recipients of blood components and organs transplant, especially those who are immunosuppressed, may reproduce the greater systemic spread and morbidity of those infected through percutaneous routes. There is a potential risk of MPXV transmission and severe disease outcomes in blood and transplant recipients. In addition to current risk assessments performed in the UK and exclusion of donors with recent MPXV exposure, determining viraemia frequencies in donors and directly evaluating transmission risk would be of considerable value in assessing whether MPXV nucleic acid screening should be implemented.

The recent emergence of the monkeypox virus (MPXV) in non-endemic countries has been designated a Public Health Emergency of International Concern by the World Health Organization. There are currently no approved treatments for MPXV infection in the United States or Canada. The antiviral drug tecovirimat (commonly called TPOXX), previously approved for smallpox treatment, is currently being deployed for treatment of MPXV infections where available based on previously accrued data. We tested the efficacy of TPOXX both in vitro and in vivo against a clade 2 Canadian 2022 isolate of MPXV isolated during the current outbreak. TPOXX prevented MPXV replication in vitro with an effective concentration in the nanomolar range. To evaluate TPOXX efficacy in vivo, we first characterized the CAST/EiJ mouse model with the same 2022 Canadian isolate. Unlike previous descriptions of this model, the Canadian isolate was not lethal in CAST/EiJ mice, although it replicated efficiently in the respiratory tract after intranasal infection. Subsequent experiments demonstrated that daily oral TPOXX treatment markedly reduced viral titers in the tissues 1 and 2 weeks after infection. Our data indicate that TPOXX is highly effective against currently circulating MPXV strains and could be an important contributor to curbing the ongoing outbreak.

Monkeypox is a viral zoonotic disease on the rise across endemic habitats. Despite the growing importance of monkeypox virus, our knowledge on its host spectrum and sylvatic maintenance is limited. Here, we describe the recent repeated emergence of monkeypox virus in a wild, human-habituated western chimpanzee (Pan troglodytes verus, hereafter chimpanzee) population from Taï National Park, Ivory Coast. Through daily monitoring, we show that further to causing its typical exanthematous syndrome, monkeypox can present itself as a severe respiratory disease without a diffuse rash. By analysing 949 non-invasively collected samples, we identify the circulation of at least two distinct monkeypox virus lineages and document the shedding of infectious particles in faeces and flies, suggesting that they could mediate indirect transmission. We also show that the carnivorous component of the Taï chimpanzees' diet, mainly consisting of the sympatric monkeys they regularly hunt, did not change nor shift towards rodent consumption (the presumed reservoir) before the outbreaks, suggesting that the sudden emergence of monkeypox virus in this population is probably due to changes in the ecology of the virus itself. Using long-term mortality surveillance data from Taï National Park, we provide evidence of little to no prior viral activity over at least two decades. We conclude that great ape sentinel systems devoted to the longitudinal collection of behavioural and health data can help clarify the epidemiology and clinical presentation of zoonotic pathogens.

In vitro and in vivo models for monkeypox

The emergence of the monkeypox virus (MPXV) outbreak in 2022 is a worldwide health issue. The rapid increase of monkeypox cases caused the WHO to designate the escalating global monkeypox outbreak a Public Health Emergency of International Concern on July 23, 2022. The WHO has called on the group currently most affected by the virus, men who have sex with men (MSM), to limit their sexual partners. The diminution in number of sexual partners not only decreases the proportion of infected MSM but could also increases the number of days needed to reach a given infection level among the general population. Several behavioral factors could be associated with high levels of different sexual partners, such as cannabis use and alcohol consumption. Firstly, this review focuses on the association between cannabis and alcohol consumption and the number of sexual partners, and their possible impact on the current MPXV outbreak by impairing the immune responses. Secondly, this review investigated in the UK Biobank cohort the relationship between alcohol and cannabis use and the number of sexual partners. Among the 115,604 participants, 1.8% declared to be MSM, 1.9% to be WSW (women having sex with women), 43.3% men heterosexuals and 53.0% women heterosexuals. MSM and WSW showed higher lifetime sexual partners (N = 17.4 (SD:17.52) and N = 13.65 (SD: 13.21), respectively) compared to heterosexual men (N = 6.89 (SD: 9.47) and women (N = 5.19 (SD:6.56), p < 0.001. After adjustment for age, body mass index, lifetime sexual activity, educational and income levels, tobacco and cardiovascular diseases, cannabis use and alcohol consumption remained significantly associated with increase in the number of different sexual partners in all four subgroups. Thus, cannabis use and alcohol consumption may have two detrimental effects on the MPXV outbreak: by participating in the increase of the number of sexual partners which are mainly responsible for the augmentation of the number of new MPXV infected cases and by impairing the immune response to a viral infection. Health and safety policies should address the factors and practices, including chemsex, leading to an increase in risk of sexual behaviors responsible for MPXV dissemination in the worldwide population.

The recent emergence and global spread of the human Monkeypox virus (MPXV), including its transmission to non-endemic regions, have raised significant global health concerns. In this proof-of-concept study, we developed a recombinant protein-based MPXV vaccine candidate, employing an innovative and versatile multivalent, self-assembled nanocage protein scaffold. Two immunogenic antigens derived from the contemporary circulating MPXV strain have been incorporated into a self-assembled non-structural protein-10 (NSP-10) scaffold, expressed, and purified using an Escherichia coli expression system without a purification tag. The vaccine candidate elicited strong antibody responses in mice and conferred protection against the lethal Vaccinia virus in an intranasal and skin pock in vivo study. Additionally, an intranasal challenge with the MPXV strain clade IIb in immunized mice demonstrated promising outcomes, including a significant reduction in viral titres and eliciting a robust neutralizing antibody response. This study demonstrates a feasible, scalable, and cost-effective approach for the development of the MPXV vaccine.

A single-dose nanoparticle vaccine protects against mpox in preclinical models.

In response to the emergence of the monkeypox virus (MPXV) in Australia in May 2022, we developed and evaluated indirect immunofluorescence assays (IFA) for MPXV and Vaccinia virus (VACV) IgG and IgM antibodies using serum samples from patients with nucleic acid amplification test (NAAT)-confirmed mpox and uninfected unvaccinated controls. Additionally, 47 healthcare workers receiving two doses of the third-generation smallpox vaccine Modified Vaccinia Ankara-Bavarian Nordic (MVA-BN) undertook serial serum collection to describe the serological response to vaccination. MPXV antibodies were detected in 16/18 individuals with NAAT-confirmedmpox (sensitivity 0.89, specificity 1.00), and VACV antibodies were detected in 28/29 individuals who received two doses of MVA-BN vaccine (sensitivity 0.97, specificity 1.00). Detectable antibody in subjects historically vaccinated with early-generation vaccines against smallpox was found in 7/7 subjects, at a median of 48 years following vaccination. MPXVNAAT-positivepatients with serum samples collected within the first 14 days after rash onset had detectable IgG and IgM in 9/12 and 5/12 of patients, respectively, with maintenance of IgG and disappearance of IgM titersafter 60 days. Whilespecificity was high when testing unvaccinated and uninfected subjects, significant cross-reactivity between MPXV and VACV antibodies was observed.

The emergence and rapid evolution of human pathogenic viruses, combined with the difficulties in developing effective vaccines, underline the need to develop innovative broad-spectrum antiviral therapeutic agents. The present study aims to determine the in silico antiviral potential of six bacterial antimicrobial peptides (AMPs), two phytochemicals (silvestrol, andrographolide), and two bacterial secondary metabolites (lyngbyabellin A, hapalindole H) against dengue virus, Zika virus, Ebola virus, the major variants of SARS-CoV-2 and monkeypox virus. The comparison of docking scores obtained with natural biomolecules was performed with specific neutralizing antibodies (positive controls for ClusPro) and antiviral drugs (negative controls for Autodock Vina). Glycocin F was the only natural biomolecule tested to show high binding energies to all viral surface proteins and the corresponding viral cell receptors. Lactococcin G and plantaricin ASM1 also achieved high docking scores with all viral surface proteins and most corresponding cell surface receptors. Silvestrol, andrographolide, hapalindole H, and lyngbyabellin A showed variable docking scores depending on the viral surface proteins and cell receptors tested. Three glycocin F mutants with amino acid modifications showed an increase in their docking energy to the spike proteins of SARS-CoV-2 B.1.617.2 Indian variant, and of the SARS-CoV-2 P.1 Japan/Brazil variant, and the dengue DENV envelope protein. All mutant AMPs indicated a frequent occurrence of valine and proline amino acid rotamers. AMPs and glycocin F in particular are the most promising biomolecules for the development of broad-spectrum antiviral treatments targeting the attachment and entry of viruses into their target cell.

Pandemic represents challenging medical emergency as it is usually associated with high rates of mortalities and morbidities. Along the last 2 and half years the world has faced the emergence of severe acute respiratory syndrome corona virus 2 pandemic that caught medical agencies and health authorities by surprise and costed more than half billion morbidities and 6 million mortalities. Unfortunately, the way developed countries contained the novel corona virus was unsatisfactory in means of early quarantines as well as obtaining and distributing an effective vaccine. This failure in management might have been responsible for the emergence of a new potential pandemic caused by monkeypox virus. Along the current review article, a detailed comparison is presented between corona virus and monkeypox virus based on virological characteristics, role of corona virus in monkeypox spread, pathogenesis, neuropsychiatric manifestations, and treatment and management. It is obvious that both viruses have a major role in causing various neuropsychiatric manifestations. Neurological manifestations are either bound directly to the virus spread to central and peripheral nervous system or secondary to triggering an immune reaction. Psychiatric ones are mostly related to stigmatization, isolation as well as changes that takes place in neurotransmitters and their metabolites within the nervous system. Dealing properly with monkeypox virus spread through previously learned lessons from corona virus might protect the world from a new pandemic.

Currently, in addition to the COVID-19 waves, the world is confronting an additional threat: the global monkeypox infection outbreak, already regarded as a “public health emergency of international concern” by the World Health Organization. According to the most recently published reports, more than 21000 monkeypox infection cases have been confirmed in 78 countries, with 5 African deaths and more than three deaths outside endemic Africa while the numbers are still increasing. Too little is currently known about the monkeypox virus, although it does not appear as a recently emerged pathogen, being probably as ancient as the smallpox virus. The major fear in regards to the current international monkeypox infection spread has multiple causes: monkeypox's similarity to smallpox, the deadliest pathogen in the history of humanity; lack of knowledge of the virus's natural occurrence, animal reservoir, mechanisms of transmission, pathogenicity, host immune response; lack of effective specific treatment and vaccine; unusually rapid geographic spread and atypical clinical presentation; increase in the mutation rate outside the standard, mathematically anticipated rates; putative complications and sequelae of the infection; potential use as a biological weapon. Actually, with such characteristics, the monkeypox virus has the potential to occupy/replicate the place of the much-feared smallpox virus. In the near future, due to the high registry of viral mutagenesis, limitations in the preventive strategies, and lack of an efficient vaccine, several viruses, including SARS-CoV-2 and monkeypox, could continue their worldwide spread and generate flu-like subsequent infective bursts. Therefore, dedicated research and detailed knowledge of the viral pathogenic mechanisms and transmission routes are required to design efficient therapies and limit/stop future pandemics: until the emergence of a new virus.