How does the influenza virus replicate?
Abstract Influenza viruses replicate within the nucleus of the host cell. This uncommon RNA virus trait provides influenza with the advantage of access to the nuclear machinery during replication. However, it also increases the complexity of the intracellular trafficking that is required for the viral components to establish a productive infection.
Why does the influenza virus have access to the nuclear machinery?
This uncommon RNA virus trait provides influenza with the advantage of access to the nuclear machinery during replication. However, it also increases the complexity of the intracellular trafficking that is required for the viral compon … Influenza viruses replicate within the nucleus of the host cell.
What is the genome of influenza A made up of?
The genome of influenza A virus consists of eight segments of negative-strand viral RNA (vRNA). During the replication cycle of the virus, the genomic vRNA is transcribed into positive-strand mRNA and complementary RNA (cRNA) in the cell nucleus.
Why does influenza have a unique RNA virus structure?
This uncommon RNA virus trait provides influenza with the advantage of access to the nuclear machinery during replication. However, it also increases the complexity of the intracellular trafficking that is required for the viral components to establish a productive infection.
How do influenza viruses replicate?
0:134:55Influenza virus replication Cycle Animation - YouTubeYouTubeStart of suggested clipEnd of suggested clipThe flu is a contagious respiratory infection caused by influenza viruses like all viruses influenzaMoreThe flu is a contagious respiratory infection caused by influenza viruses like all viruses influenza must gain entry into host cells to replicate. The process involves several stages from attachment
On which cells does the influenza virus attach and replicate?
The influenza virus enters the host cell by having its hemagglutinin bind to the sialic acid found on glycoproteins or glycolipid receptors of the host. The cell then endocytoses the virus. In the acidic environment of the endosomes, the virus changes shape and fuses its envelope with the endosomal membrane.
Does influenza replicate in the cytosol?
Influenza A is an RNA virus, meaning that it reproduces itself inside the nucleus. Most viruses replicate in a cell's cytoplasm, outside the nucleus.
Where does the influenza virus come from?
Most influenza viruses that infect humans seem to originate in parts of Asia, where close contact between livestock and people creates a hospitable environment for mutation and transmission of viruses.
How does influenza grow and reproduce?
The influenza virus life cycle can be divided into the following stages: entry into the host cell; entry of vRNPs into the nucleus; transcription and replication of the viral genome; export of the vRNPs from the nucleus; and assembly and budding at the host cell plasma membrane.
How does a virus replicate?
Viruses cannot replicate on their own, but rather depend on their host cell's protein synthesis pathways to reproduce. This typically occurs by the virus inserting its genetic material in host cells, co-opting the proteins to create viral replicates, until the cell bursts from the high volume of new viral particles.
Do viruses replicate in the nucleus?
All DNA viruses replicate within the nucleus except poxviruses, asfarviruses, and phycodnaviruses. Few RNA viruses, including bornaviruses, orthomyxoviruses, and retroviruses, replicate in the nucleus.
Where does influenza live in the body?
Influenza is a viral infection that attacks your respiratory system — your nose, throat and lungs.
What cells does the influenza virus infect?
Influenza virus infects respiratory epithelial cells that line the upper (including nasal) through lower (to the alveoli) respiratory tract. A key parameter in determining the extent of associated disease is the degree to which the lower respiratory tract becomes invaded by the virus [7].
How did the first flu start?
It was caused by an H1N1 virus with genes of avian origin. Although there is not universal consensus regarding where the virus originated, it spread worldwide during 1918-1919. In the United States, it was first identified in military personnel in spring 1918.
When and where does influenza occur more commonly?
In temperate climates, seasonal epidemics occur mainly during winter, while in tropical regions, influenza may occur throughout the year, causing outbreaks more irregularly. The time from infection to illness, known as the incubation period, is about 2 days, but ranges from one to four days.
Why does the flu always come from Asia?
Seasonality: 85 percent of Asia's population lives in tropical or subtropical regions with no distinct winter, allowing continuous transmission of endemic flu strains and more opportunities for evolution of new strains.
How does influenza virus attach to cells?
The viruses attach to cells within the nasal passages and throat (i.e., the respiratory tract). The influenza virus's hemagglutinin (HA) surface proteins then bind to the sialic acid receptors on the surface of a human respiratory tract cell.
Which structure on the influenza virus provides attachment to the surface of the targeted host cell?
The glycoprotein responsible for attachment on the surface of an influenza viral particle is hemagglutinin (HA). HA is an antigenic glycoprotein. It is responsible for binding the virus to the cell that is being infected.
What receptors do viruses attach to?
Common viral receptors include sialylated glycans, cell adhesion molecules such as immunoglobulin superfamily members and integrins, and phosphatidylserine receptors.
What type of cells are infected by the flu?
Influenza viruses primarily target airway epithelial cells via α2,3- and α2,6-type receptors, but the distribution of these receptors in many species is uncertain and may be a significant factor influencing infection.
What happens during the replication cycle of a virus?
During the replication cycle of the virus, a "switch" from mRNA to cRNA synthesis occurs, but the mechanism by which this switch occurs remains unclear. The viral nucleoprotein and its interaction with the polymerase proteins and vRNA might play a role in this process.
Where is vRNA transcribed?
During the replication cycle of the virus, the genomic vRNA is transcribed into positive-strand mRNA and complementary RNA (cRNA) in the cell nucleus. The promoter for the synthesis of mRNA molecules is l …. The genome of influenza A virus consists of eight segments of negative-strand viral RNA (vRNA). During the replication cycle of the virus, the ...
Where is the promoter located in mRNA?
The promoter for the synthesis of mRNA molecules is located in a partially double-stranded RNA structure formed by the 5'- and 3'-terminal sequences of genomic vRNA segments.
What is the name of the change in the surface proteins of the virus?
One way influenza viruses change is called “antigenic drift.”. These are small changes (or mutations) in the genes of influenza viruses that can lead to changes in the surface proteins of the virus: HA (hemagglutinin) and NA (neuraminidase).
What happens when viruses drift?
The small changes that occur from antigenic drift usually produce viruses that are closely related to one another, which can be illustrated by their location close together on a phylogenetic tree. Influenza viruses that are closely related to each other usually have similar antigenic properties.
What is it called when the immune system recognizes and responds to a virus?
This means that antibodies your immune system creates against one influenza virus will likely recognize and respond to antigenically similar influenza viruses (this is called “cross-protection”). However, the small changes associated with antigenic drift can accumulate over time and result in viruses that are antigenically different ...
What happens when antigenic drift occurs?
When antigenic drift occurs, the body’s immune system may not recognize and prevent sickness caused by the newer influenza viruses. As a result, a person becomes susceptible to flu infection again, as antigenic drift has changed the virus enough that a person’s existing antibodies won’t recognize and neutralize the newer influenza viruses.
What is the influenza virus?
Influenza is a communicable viral disease that affects the upper respiratory tract, including upper and lower respiratory passages. A wide spectrum of influenza viruses causes it. Some of these viruses can infect humans, and some are specific to different species. This activity reviews the pathophysiology of influenza and highlights the role of the interprofessional team in its prevention and treatment.
How does the flu affect people?
Each year, the flu affects millions of people and lead to time off work and school. The symptoms seriously affect the quality of life, and at extremes of age, the infection is known to cause death,
What is the best team for influenza?
The prevention and treatment of influenza are best done with an interprofessional team that includes a nurse, nurse practitioner, primary care provider, internist, pharmacist, an emergency department physician, and an infectious disease specialist.
What is the importance of influenza A?
An important aspect of influenza A virus is that it is a genetically labile virus with a high rate of mutations. This results in major changes in antigenic and functional proteins.
What tests are available for influenza?
Laboratory tests available for diagnosis of influenza are rapid antigen detection, a rapid molecular assay for the detection of viral RNA, immunofluorescence direct and indirect antibody staining for detection of viral antigen, real-time PCR test, and cell culture.
What are the symptoms of influenza?
Signs and symptoms of influenza in mild cases include a cough, fever, sore throat, myalgia, headache, runny nose, and congested eyes. A frontal or retro-orbital headache is a common presentation with selected ocular symptoms that include photophobia and pain with different qualities. The cause of ocular pain is related to the viral tropism that is associated with certain types and subtypes. Severe cases may progress to shortness of breath, tachycardia, hypotension, and need for supportive respiratory interventions in as little as 48 hours.
Can PCR test detect influenza?
Over the past few decades, more lethal strains of the influenza virus have evolved. Besides infecting humans, these viruses also infect animals. Clinicians should be aware that all rapid tests for detecting influenza have limited sensitivity, and false-negative results are common. The gold standard for diagnosis is the PCR test or viral culture of throat secretions, but these tests take a few days to yield results. The key strategy in reducing the morbidity of the infection is vaccination.
Where does Influenza A replicate?
Influenza A is an RNA virus, meaning that it reproduces itself inside the nucleus. Most viruses replicate in a cell's cytoplasm, outside the nucleus.
What is the mechanism of influenza A?
Now, a research team headed by investigators from the Icahn School of Medicine at Mount Sinai is the first to identify a mechanism by which influenza A, a family of pathogens that includes the most deadly strains ...
How did the investigators understand how influenza A hijacks the RNA exosome inside a cell's nu?
It was by studying the cells of patients with an RNA exosome mutation, which were contributed by six collabora ting medical centers, that the investigators were able to understand how influenza A hijacks the RNA exosome inside a cell's nucleus for its own purposes.
What is the type of influenza?
Influenza viruses belong to the Orthomyxoviridaefamily and are classified as either type A, B, C, or the recently identified type D (1, 2) . Influenza A viruses (IAVs) and type B viruses (IBVs) contain 8, negative-sense, single-stranded viral RNA (vRNA) gene segments (Figure (Figure1A)1A) (3, 4), which encode transcripts for 10 essential viral proteins, as well as several strain-dependent accessory proteins (Figure (Figure1B).1B). In comparison, influenza type C and D viruses only possess seven vRNA gene segments, as the hemagglutinin–esterase fusion protein vRNA replaces the hemagglutinin (HA or H) and the neuraminidase (NA or N) vRNAs (1, 2). IAVs will be the main focus of this review since they are the primary agents responsible for influenza pandemics, and a major contributor to the annual influenza epidemics in the human population (5).
How does vrNP enter the nucleus?
In contrast to the early steps in IAV entry, vRNP trafficking to the nucleus following the fusion event is highly dependent on the host cell machinery and transport pathways [reviewed in Ref. (76)]. Supported by numerous studies, the current model is that the newly released cytoplasmic vRNPs use the importin-α–importin-β nuclear import pathway to gain entry to the host cell nucleoplasm (Figure (Figure2B,2B, steps vi and vii) (77–83). To initially engage this pathway, it is thought that the vRNPs use the surface exposed nuclear localization sequences from the numerous NP molecules to recruit the adapter protein importin-α (80–82). Upon binding to the vRNP, importin-α is recognized by the importin-β transport receptor, which directs the vRNP to the nuclear pore complex, where it is transported into the nucleoplasm.
How does mRNA transcription work?
Transcription of IAV mRNAs by the viral polymerase. Viral mRNA transcription occurs when the viral ribonucleoproteins reach the host cell nucleus and is assisted by the association of the viral polymerase (PA subunit) with the cellular RNA polymerase II C-terminal domain (RNA pol II CTD). Transcription initiates by a “cap-snatching” mechanism where the PB2 subunit binds to the 5′ cap of a host mRNA (red). Cap binding positions the region of the mRNA 10–13 nucleotides downstream for cleavage by the endonuclease domain in the PA subunit. Following cleavage, a conformational shift repositions the acquired mRNA capped primer to the PB1 subunit where the 3′ end base-pairs with a complimentary sequence at the vRNA 3′ end. Following the priming event, the viral polymerase extends the mRNA transcript. The transcription is terminated by a “reiterative stuttering” process (depicted in the box), which occurs when the polymerase encounters the 5–7 consecutive uracil bases at the vRNA 5′ end. The “reiterative stuttering” function likely involves multiple cycles of dissociation and reannealing, and effectively polyadenylates [A(n)] the viral mRNA by continuously repositioning the elongating 3′ end on the uracil-rich region of the vRNA template.
How long does it take for a vRNA to enter the nucleus?
The cumulative results from these studies show that IAVs can deliver their vRNPs from the cell surface to the nucleus in approximately 1 h, with entry and fusion occurring rather quickly (~10 min), and nuclear import requiring the bulk of the time (85). A striking observation from these studies is the efficiency with which the eight vRNAs reach the nucleus, indicating how effectively vRNPs recruit the host nuclear import factors. Supporting this observation, it was shown that NP adaptation to the importin-α isoforms of a particular species is crucial for productive IAV infections (86). While the bulk of the vRNP trafficking work has been carried out using various immortalized cell lines, the potential species related differences, and the essential role of vRNP trafficking in reassortment, emphasize the need for further methodology development to examine the details of IAV entry in primary cells and tissue explants.
How do IAVs get into the host cell?
IAVs initiate the infection process by using the HA molecules on the viral envelope. Upon reaching a potential host cell, the HA receptor-binding site attaches the virus to surface glycoconjugates that contain terminal SA residues (Figure (Figure2A)2A) (18, 48, 49). IAVs then scan the cell surface for the proper sialylated “receptor” by using the sialidase function of NA to remove local SAs and liberate nonproductive HA associations (50). Currently, the “receptor’s” identity remains unknown, but it is generally thought that HAs from avian IAVs have higher specificity for receptors with α-2,3-linked SAs that have a “linear” presentation (51, 52), whereas HAs from human IAVs prefer an α-2,6 linkage, which results in a more “bent” presentation (Figure (Figure2A)2A) (53, 54). While these preferences correlate with SA linkages in the respective hosts (55), several studies have shown that matching HA receptor binding preferences with the SA linkages in a particular host is not essential for infection, but is more critical for transmission (56–59). This implies that the IAV “receptor” either displays significant cell tropism in the airways or that IAVs can potentially use more than one receptor.
What is the constant evolution of surface antigens?
A significant challenge in battling IAVs is the constant evolution of the surface antigens (HA and NA) in response to pressure from the host immune system, which is referred to as antigenic drift and antigenic shift . Antigenic drift is most evident in circulating seasonal IAVs, where substitutions by the polymerase that cause mutations in the surface antigen epitopes have continuously been selected to enable reinfection of the same host (45). Antigenic shift is responsible for the development of the IAV pandemics, and it relies on the less frequent process of reassortment, which involves the exchange of vRNAs between two IAVs during co-infection of a cell (43, 46, 47). While reassortment can happen between two related IAVs, antigenic shift occurs when the reassortment process yields a new IAV subtype.
Where are vrNPs transported?
Within the cytoplasm the vRNPs are trafficked toward the plasma membrane for viral assembly by Rab11. Rab11 facilitates the interaction by associating with the viral polymerase PB2 subunit (130), potentially providing a quality control mechanism that ensures new virions incorporate vRNPs carrying a polymerase. Earlier studies proposed that vRNPs specifically associate with Rab11 on recycling endosomes, which use microtubules for transport toward the cell surface (Figure (Figure5,5, step xiia) (130–132). An alternative model has recently been proposed where infection causes tubulation of the ER membrane network and the vRNPs bind to Rab11 molecules that have localized to this network for trafficking toward the plasma membrane (Figure (Figure5,5, step xiib) (133). Currently, it is not known how vRNPs are transferred to the plasma membrane in either model, or how IAVs incorporate all eight of the different vRNPs in a “1 + 7” configuration. While several studies have indicated that specific vRNP associations likely contribute to the packaging of the eight vRNPs (35, 134, 135), the underlying mechanisms remain to be established.
