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Difficulty: MediumInfectious Disease Mechanisms

A 24-year-old medical resident presents to the occupational health clinic in late January with sudden-onset high fever, severe myalgias, dry cough, and profound fatigue. She notes several of her patients had similar symptoms over the past week. A rapid point-of-care test confirms infection with an enveloped, negative-sense, single-stranded RNA virus with a segmented genome. The pathogen relies on a specific sequence of molecular events to successfully invade respiratory epithelial cells. Arrange the following steps of this virus's early entry and uncoating mechanism in the correct chronological order, from initial host cell contact to the delivery of its genetic material for replication.

  1. 1Viral surface glycoprotein binds to host cell sialic acid residues
  2. 2Invagination of the host cell membrane and formation of a virus-containing endosome
  3. 3Influx of protons into the virion interior via viral M2 ion channels
  4. 4Conformational change of the viral surface glycoprotein triggering envelope-endosome membrane fusion
  5. 5Translocation of viral ribonucleoproteins from the cytoplasm into the host nucleus

Answer

The correct sequence for influenza virus entry is: 1) Viral surface glycoprotein binds to host cell sialic acid residues. 2) Invagination of the host cell membrane and formation of a virus-containing endosome. 3) Influx of protons into the virion interior via viral M2 ion channels. 4) Conformational change of the viral surface glycoprotein triggering envelope-endosome membrane fusion. 5) Translocation of viral ribonucleoproteins from the cytoplasm into the host nucleus.
Influenza infection begins when viral Hemagglutinin (HA) binds to sialic acid on the respiratory epithelium. This triggers receptor-mediated endocytosis. Inside the host cell, the endosome undergoes natural acidification. The low pH environment activates the viral M2 ion channel, which pumps protons into the virion to dissociate the viral matrix. Simultaneously, the acidic pH causes a conformational change in HA, mediating fusion between the viral envelope and the endosomal membrane. Finally, the uncoated viral ribonucleoproteins are released into the cytoplasm and translocated into the nucleus, a unique step for orthomyxoviruses, allowing replication to begin.

Step-by-Step Solution

1
Identify the specific pathogen described in the vignette.
The patient has influenza, caused by the influenza virus (an enveloped, negative-sense, segmented ssRNA virus).
Recognizing the pathogen dictates the specific molecular mechanism of its infectious cascade.
2
Determine the initial event of viral infection.
The virus must first attach to the host cell via hemagglutinin binding to sialic acid.
Without surface receptor binding, the virus cannot initiate cellular entry.
3
Identify the method of cellular uptake.
The virus is internalized via receptor-mediated endocytosis.
Attachment triggers the host cell membrane to invaginate, trapping the virion in an endosome.
4
Trace the intracellular triggers for uncoating.
The endosome acidifies, leading to proton influx through the M2 channel and HA conformational changes.
The low pH environment is required to drive both the dissociation of internal viral proteins and the fusion of membranes.
5
Determine the final destination of the viral genome prior to replication.
The viral ribonucleoproteins (vRNPs) enter the host nucleus.
Unlike most RNA viruses, orthomyxoviruses replicate in the nucleus and require nuclear import of their genetic material.

Key Concept

Influenza virus entry and uncoating cascade
Estimated Time:1m 30s
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Topics

Infectious Disease Mechanisms

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