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American Family Physician Dec 2019Influenza is an acute viral respiratory infection that causes significant morbidity and mortality worldwide. Three types of influenza cause disease in humans. Influenza...
Influenza is an acute viral respiratory infection that causes significant morbidity and mortality worldwide. Three types of influenza cause disease in humans. Influenza A is the type most responsible for causing pandemics because of its high susceptibility to antigenic variation. Influenza is highly contagious, and the hallmark of infection is abrupt onset of fever, cough, chills or sweats, myalgias, and malaise. For most patients in the outpatient setting, the diagnosis is made clinically, and laboratory confirmation is not necessary. Laboratory testing may be useful in hospitalized patients with suspected influenza and in patients for whom a confirmed diagnosis will change treatment decisions. Rapid molecular assays are the preferred diagnostic tests because they can be done at the point of care, are highly accurate, and have fast results. Treatment with one of four approved anti-influenza drugs may be considered if the patient presents within 48 hours of symptom onset. The benefit of treatment is greatest when antiviral therapy is started within 24 hours of symptom onset. These drugs decrease the duration of illness by about 24 hours in otherwise healthy patients and may decrease the risk of serious complications. No anti-influenza drug has been proven superior. Annual influenza vaccination is recommended for all people six months and older who do not have contraindications.
Topics: Antiviral Agents; Humans; Influenza Vaccines; Influenza, Human
PubMed: 31845781
DOI: No ID Found -
Cells May 2023The development of antiretroviral drugs (ARVs) was a great milestone in the management of HIV infection. ARVs suppress viral activity in the host cell, thus minimizing... (Review)
Review
The development of antiretroviral drugs (ARVs) was a great milestone in the management of HIV infection. ARVs suppress viral activity in the host cell, thus minimizing injury to the cells and prolonging life. However, an effective treatment has remained elusive for four decades due to the successful immune evasion mechanisms of the virus. A thorough understanding of the molecular interaction of HIV with the host cell is essential in the development of both preventive and curative therapies for HIV infection. This review highlights several inherent mechanisms of HIV that promote its survival and propagation, such as the targeting of CD4 lymphocytes, the downregulation of MHC class I and II, antigenic variation and an envelope complex that minimizes antibody access, and how they collaboratively render the immune system unable to mount an effective response.
Topics: Humans; HIV Infections; HIV-1; Immune System; Genes, MHC Class I
PubMed: 37408185
DOI: 10.3390/cells12101351 -
Annual Review of Pathology Jan 2023African trypanosomes are bloodstream protozoan parasites that infect mammals including humans, where they cause sleeping sickness. Long-lasting infection is required to... (Review)
Review
African trypanosomes are bloodstream protozoan parasites that infect mammals including humans, where they cause sleeping sickness. Long-lasting infection is required to favor parasite transmission between hosts. Therefore, trypanosomes have developed strategies to continuously escape innate and adaptive responses of the immune system, while also preventing premature death of the host. The pathology linked to infection mainly results from inflammation and includes anemia and brain dysfunction in addition to loss of specificity and memory of the antibody response. The serum of humans contains an efficient trypanolytic factor, the membrane pore-forming protein apolipoprotein L1 (APOL1). In the two human-infective trypanosomes, specific parasite resistance factors inhibit APOL1 activity. In turn, many African individuals express APOL1 variants that counteract these resistance factors, enabling them to avoid sleeping sickness. However, these variants are associated with chronic kidney disease, particularly in the context of virus-induced inflammation such as coronavirus disease 2019. Vaccination perspectives are discussed.
Topics: Humans; Apolipoprotein L1; COVID-19; Inflammation; Trypanosoma brucei rhodesiense; Trypanosomiasis, African
PubMed: 36055769
DOI: 10.1146/annurev-pathmechdis-031621-025153 -
Cell Mar 2023Cancer immunotherapies, including adoptive T cell transfer, can be ineffective because tumors evolve to display antigen-loss-variant clones. Therapies that activate...
Cancer immunotherapies, including adoptive T cell transfer, can be ineffective because tumors evolve to display antigen-loss-variant clones. Therapies that activate multiple branches of the immune system may eliminate escape variants. Here, we show that melanoma-specific CD4 T cell therapy in combination with OX40 co-stimulation or CTLA-4 blockade can eradicate melanomas containing antigen escape variants. As expected, early on-target recognition of melanoma antigens by tumor-specific CD4 T cells was required. Surprisingly, complete tumor eradication was dependent on neutrophils and partly dependent on inducible nitric oxide synthase. In support of these findings, extensive neutrophil activation was observed in mouse tumors and in biopsies of melanoma patients treated with immune checkpoint blockade. Transcriptomic and flow cytometry analyses revealed a distinct anti-tumorigenic neutrophil subset present in treated mice. Our findings uncover an interplay between T cells mediating the initial anti-tumor immune response and neutrophils mediating the destruction of tumor antigen loss variants.
Topics: Mice; Animals; T-Lymphocytes; Neutrophils; Antigenic Drift and Shift; Immunotherapy; Melanoma; CTLA-4 Antigen
PubMed: 37001503
DOI: 10.1016/j.cell.2023.03.007 -
Nature Reviews. Microbiology Jul 2021Although most mutations in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome are expected to be either deleterious and swiftly purged or relatively... (Review)
Review
Although most mutations in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome are expected to be either deleterious and swiftly purged or relatively neutral, a small proportion will affect functional properties and may alter infectivity, disease severity or interactions with host immunity. The emergence of SARS-CoV-2 in late 2019 was followed by a period of relative evolutionary stasis lasting about 11 months. Since late 2020, however, SARS-CoV-2 evolution has been characterized by the emergence of sets of mutations, in the context of 'variants of concern', that impact virus characteristics, including transmissibility and antigenicity, probably in response to the changing immune profile of the human population. There is emerging evidence of reduced neutralization of some SARS-CoV-2 variants by postvaccination serum; however, a greater understanding of correlates of protection is required to evaluate how this may impact vaccine effectiveness. Nonetheless, manufacturers are preparing platforms for a possible update of vaccine sequences, and it is crucial that surveillance of genetic and antigenic changes in the global virus population is done alongside experiments to elucidate the phenotypic impacts of mutations. In this Review, we summarize the literature on mutations of the SARS-CoV-2 spike protein, the primary antigen, focusing on their impacts on antigenicity and contextualizing them in the protein structure, and discuss them in the context of observed mutation frequencies in global sequence datasets.
Topics: Amino Acids; Antigenic Variation; COVID-19; COVID-19 Vaccines; Epitopes; Humans; Immune Evasion; Mutation; Protein Conformation; SARS-CoV-2; Spike Glycoprotein, Coronavirus
PubMed: 34075212
DOI: 10.1038/s41579-021-00573-0 -
Frontiers in Immunology 2020Protective vaccines for hypervariable pathogens are urgently needed. It has been proposed that amputating highly variable epitopes from vaccine antigens would induce the...
Protective vaccines for hypervariable pathogens are urgently needed. It has been proposed that amputating highly variable epitopes from vaccine antigens would induce the production of broadly protective antibodies targeting conserved epitopes. However, so far, these approaches have failed, partially because conserved epitopes are occluded and partially because co-localizing patterns of immunodominance and antigenic variability render variable epitopes the primary target for antibodies in natural infection. In this Perspective, to recast the challenge of vaccine development for hypervariable pathogens, I evaluate convergent mechanisms of adaptive variation, such as intrahost immune-mediated diversification, spatiotemporally defined antigenic space, and infection-enhancing cross-immunoreactivity. The requirements of broadly protective immune responses targeting variable pathogens are formulated in terms of cross-immunoreactivity, stoichiometric thresholds for neutralization, and the elicitation of antibodies targeting physicochemically conserved signatures within sequence variable domains.
Topics: Animals; Antibodies, Neutralizing; Antigenic Variation; Humans; Immunodominant Epitopes; Mutation; Vaccination; Viral Envelope Proteins; Viral Vaccines; Virus Diseases
PubMed: 33013870
DOI: 10.3389/fimmu.2020.02057 -
Nature Feb 2023Continuous evolution of Omicron has led to a rapid and simultaneous emergence of numerous variants that display growth advantages over BA.5 (ref. ). Despite their...
Continuous evolution of Omicron has led to a rapid and simultaneous emergence of numerous variants that display growth advantages over BA.5 (ref. ). Despite their divergent evolutionary courses, mutations on their receptor-binding domain (RBD) converge on several hotspots. The driving force and destination of such sudden convergent evolution and its effect on humoral immunity remain unclear. Here we demonstrate that these convergent mutations can cause evasion of neutralizing antibody drugs and convalescent plasma, including those from BA.5 breakthrough infection, while maintaining sufficient ACE2-binding capability. BQ.1.1.10 (BQ.1.1 + Y144del), BA.4.6.3, XBB and CH.1.1 are the most antibody-evasive strains tested. To delineate the origin of the convergent evolution, we determined the escape mutation profiles and neutralization activity of monoclonal antibodies isolated from individuals who had BA.2 and BA.5 breakthrough infections. Owing to humoral immune imprinting, BA.2 and especially BA.5 breakthrough infection reduced the diversity of the neutralizing antibody binding sites and increased proportions of non-neutralizing antibody clones, which, in turn, focused humoral immune pressure and promoted convergent evolution in the RBD. Moreover, we show that the convergent RBD mutations could be accurately inferred by deep mutational scanning profiles, and the evolution trends of BA.2.75 and BA.5 subvariants could be well foreseen through constructed convergent pseudovirus mutants. These results suggest that current herd immunity and BA.5 vaccine boosters may not efficiently prevent the infection of Omicron convergent variants.
Topics: Humans; Antibodies, Monoclonal; Antibodies, Neutralizing; Antibodies, Viral; Breakthrough Infections; COVID-19; COVID-19 Serotherapy; Immunity, Humoral; SARS-CoV-2; Spike Glycoprotein, Coronavirus; Protein Domains; Antigenic Drift and Shift; Evolution, Molecular; Mutation
PubMed: 36535326
DOI: 10.1038/s41586-022-05644-7 -
Viruses Sep 2023Respiratory syncytial virus (RSV) infections are a constant public health problem, especially in infants and older adults. Virtually all children will have been infected... (Review)
Review
Respiratory syncytial virus (RSV) infections are a constant public health problem, especially in infants and older adults. Virtually all children will have been infected with RSV by the age of two, and reinfections are common throughout life. Since antigenic variation, which is frequently observed among other respiratory viruses such as SARS-CoV-2 or influenza viruses, can only be observed for RSV to a limited extent, reinfections may result from short-term or incomplete immunity. After decades of research, two RSV vaccines were approved to prevent lower respiratory tract infections in older adults. Recently, the FDA approved a vaccine for active vaccination of pregnant women to prevent severe RSV disease in infants during their first RSV season. This review focuses on the host response to RSV infections mediated by epithelial cells as the first physical barrier, followed by responses of the innate and adaptive immune systems. We address possible RSV-mediated immunomodulatory and pathogenic mechanisms during infections and discuss the current vaccine candidates and alternative treatment options.
Topics: Infant; Child; Female; Pregnancy; Humans; Aged; Respiratory Syncytial Virus Infections; Reinfection; Respiratory Syncytial Viruses; Immunity; Vaccines; Respiratory Syncytial Virus Vaccines; Respiratory Syncytial Virus, Human
PubMed: 37896776
DOI: 10.3390/v15101999 -
Clinical Microbiology Reviews Sep 2019Protozoan parasites are the causative agents of malaria, a deadly disease that continues to afflict hundreds of millions of people every year. Infections with malaria... (Review)
Review
Protozoan parasites are the causative agents of malaria, a deadly disease that continues to afflict hundreds of millions of people every year. Infections with malaria parasites can be asymptomatic, with mild or severe symptoms, or fatal, depending on many factors such as parasite virulence and host immune status. Malaria can be treated with various drugs, with artemisinin-based combination therapies (ACTs) being the first-line choice. Recent advances in genetics and genomics of malaria parasites have contributed greatly to our understanding of parasite population dynamics, transmission, drug responses, and pathogenesis. However, knowledge gaps in parasite biology and host-parasite interactions still remain. Parasites resistant to multiple antimalarial drugs have emerged, while advanced clinical trials have shown partial efficacy for one available vaccine. Here we discuss genetic and genomic studies of biology, host-parasite interactions, population structures, mosquito infectivity, antigenic variation, and targets for treatment and immunization. Knowledge from these studies will advance our understanding of malaria pathogenesis, epidemiology, and evolution and will support work to discover and develop new medicines and vaccines.
Topics: Antimalarials; Drug Resistance; Evolution, Molecular; Genome, Protozoan; Humans; Malaria; Plasmodium
PubMed: 31366610
DOI: 10.1128/CMR.00019-19 -
Nature Aug 2022Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron sublineages BA.2.12.1, BA.4 and BA.5 exhibit higher transmissibility than the BA.2 lineage. The... (Comparative Study)
Comparative Study
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron sublineages BA.2.12.1, BA.4 and BA.5 exhibit higher transmissibility than the BA.2 lineage. The receptor binding and immune-evasion capability of these recently emerged variants require immediate investigation. Here, coupled with structural comparisons of the spike proteins, we show that BA.2.12.1, BA.4 and BA.5 (BA.4 and BA.5 are hereafter referred collectively to as BA.4/BA.5) exhibit similar binding affinities to BA.2 for the angiotensin-converting enzyme 2 (ACE2) receptor. Of note, BA.2.12.1 and BA.4/BA.5 display increased evasion of neutralizing antibodies compared with BA.2 against plasma from triple-vaccinated individuals or from individuals who developed a BA.1 infection after vaccination. To delineate the underlying antibody-evasion mechanism, we determined the escape mutation profiles, epitope distribution and Omicron-neutralization efficiency of 1,640 neutralizing antibodies directed against the receptor-binding domain of the viral spike protein, including 614 antibodies isolated from people who had recovered from BA.1 infection. BA.1 infection after vaccination predominantly recalls humoral immune memory directed against ancestral (hereafter referred to as wild-type (WT)) SARS-CoV-2 spike protein. The resulting elicited antibodies could neutralize both WT SARS-CoV-2 and BA.1 and are enriched on epitopes on spike that do not bind ACE2. However, most of these cross-reactive neutralizing antibodies are evaded by spike mutants L452Q, L452R and F486V. BA.1 infection can also induce new clones of BA.1-specific antibodies that potently neutralize BA.1. Nevertheless, these neutralizing antibodies are largely evaded by BA.2 and BA.4/BA.5 owing to D405N and F486V mutations, and react weakly to pre-Omicron variants, exhibiting narrow neutralization breadths. The therapeutic neutralizing antibodies bebtelovimab and cilgavimab can effectively neutralize BA.2.12.1 and BA.4/BA.5, whereas the S371F, D405N and R408S mutations undermine most broadly sarbecovirus-neutralizing antibodies. Together, our results indicate that Omicron may evolve mutations to evade the humoral immunity elicited by BA.1 infection, suggesting that BA.1-derived vaccine boosters may not achieve broad-spectrum protection against new Omicron variants.
Topics: Angiotensin-Converting Enzyme 2; Antibodies, Monoclonal; Antibodies, Neutralizing; Antibodies, Viral; Antigenic Drift and Shift; COVID-19; COVID-19 Vaccines; Epitopes, B-Lymphocyte; Humans; Immune Tolerance; Immunity, Humoral; Immunization, Secondary; Mutation; Neutralization Tests; SARS-CoV-2; Spike Glycoprotein, Coronavirus
PubMed: 35714668
DOI: 10.1038/s41586-022-04980-y