Latency in Infection

Based on lecture slides and transcript

1. What is Latency?

• Latency is a type of infection where the pathogen remains inside the host without causing obvious disease symptoms.

• The infection is asymptomatic, meaning the person does not usually show classic signs of disease.

• Even though symptoms are absent, the infectious agent is still present inside the body.

• Latent infections can later reactivate and become active disease again.

• Latency occurs in several pathogens including:

  • viruses

  • bacteria

  • fungi

  • parasites

2. Why Do Pathogens Enter Latency?

Immune Evasion

• Latency allows pathogens to avoid detection by the immune system.

• Active replication usually produces proteins and antigens that immune cells can recognise.

• During latency, pathogens reduce these detectable activities.

• This allows long-term survival inside the host.

Survival Until Conditions Improve

• Some pathogens enter latency until conditions become favourable for replication.

• If immune pressure is high, remaining dormant may increase survival chances.

• Reactivation often occurs when immunity weakens.

3. Hallmarks of Latency

Bacterial Latency

Latently infected bacteria usually:

• reduce metabolic activity

• stop dividing

• reduce gene expression

• become tolerant to antibiotics

Viral Latency

Latently infected viruses usually:

• stop producing infectious viral particles

• stop active genome replication

• retain the viral genome inside host cells

• persist for years or decades

4. Antibiotic Tolerance in Latent Bacteria

• Many antibiotics target actively dividing bacteria.

• During latency, bacteria are metabolically inactive and not dividing.

• Therefore antibiotic targets may no longer be active.

Example

• β-lactam antibiotics target peptidoglycan synthesis.

• If bacteria are not actively synthesising cell walls, these drugs become less effective.

5. Viral Latency

Productive (Lytic) Infection

In a lytic infection:

• the virus infects the host cell

• replicates its genome

• produces viral proteins

• assembles new virions

• destroys the host cell

• spreads to neighbouring cells

Latent Infection

In latency:

• viral genomes remain inside host cells

• no active virion production occurs

• host cells survive

• the immune system often fails to detect infected cells

6. How Viruses Avoid Immune Detection During Latency

• Viral proteins needed for active replication are not produced or are produced only at very low levels.

• Some viral proteins are incorrectly localised inside the cell and cannot function properly.

• Since viral antigens are absent or reduced, infected cells evade immune recognition.

• Viral genomes can remain inside cells for years without causing active infection.

7. Fate of the Viral Genome During Latency

Different viruses use different strategies.

Integration

• Viral genome integrates into host DNA.

Non-replicative persistence

• Viral genome remains inside non-dividing cells without replicating.

Autonomous replication

• Viral genome persists independently inside the host cell.

8. Herpes Viruses

Important Human Herpes Viruses

• HSV-1

• HSV-2

• Varicella zoster virus (VZV)

Key Features

• Replicate in many tissues during active infection.

• Establish latency specifically in neurons of the peripheral nervous system.

9. Herpes Simplex Virus (HSV) Lifecycle

Active Infection

• Virus infects epithelial cells.

• Viral genome enters nucleus.

• Viral transcription and replication occur.

• Viral proteins are produced.

• New virions assemble and infect nearby cells.

Latent Infection

• Virus enters peripheral neurons.

• Viral genome remains inside neuronal nuclei.

• Productive replication genes are silenced.

• No infectious particles are produced.

10. HSV Genome During Latency

Circularisation and Histones

• Viral DNA circularises inside neurons.

• Viral genome associates with histones.

• Histones help silence viral gene expression.

Latency-Associated Transcript (LAT)

• Most viral genes are switched off during latency.

• One important region remains active:

LAT (Latency Associated Transcript)

Functions of LAT

• Helps maintain latency.

• Processed into a 2 kb intron.

• Accumulates at very high levels inside neurons.

11. MicroRNAs and HSV Latency

• HSV produces several microRNAs during latency.

• These repress transcription of lytic genes.

• This prevents production of viral proteins needed for active infection.

• Viral microRNAs may also alter host gene expression.

• Some may help prevent apoptosis of infected neurons.

12. Aberrant Localisation of Viral Proteins

VP16

• VP16 is a viral protein required for lytic replication.

• During latency it accumulates in the cytoplasm instead of the nucleus.

• Because it is not in the correct location, it cannot activate lytic gene transcription.

• This prevents production of infectious virions.

13. Host Factors Maintaining Viral Latency

mTORC1

• mTORC1 is a cellular stress sensor.

• It may suppress the lytic cycle by sequestering host factors in the cytoplasm.

Immune Cells

Surrounding cells may help maintain latency:

• CD8 T cells

• epithelial cells

• satellite glial cells

14. Reactivation of Herpes Viruses

Triggers

• stress

• trauma

• environmental factors

• weakened immunity

Example

• Trauma to trigeminal nerves can trigger herpes lesion outbreaks.

15. Varicella Zoster Virus (Chickenpox & Shingles)

Primary Infection

• VZV causes chickenpox during initial infection.

• Symptoms eventually resolve.

Latency

• Viral genome remains inside dorsal root ganglia neurons for life.

Reactivation

• Reactivation causes shingles (herpes zoster).

• Shingles causes painful lesions following nerve distribution.

Risk Factors for Reactivation

• ageing

• immunosuppression

• stress

• hot weather

16. Latent Tuberculosis Infection (LTBI)

Features

• Positive TB skin or blood test.

• Normal chest X-ray.

• Sputum negative for acid-fast bacilli.

• Patient has no symptoms.

• Patient is not infectious.

17. Biology of Latent TB

• Mycobacterium tuberculosis persists inside granulomas.

• Bacteria become:

  • non-replicating

  • metabolically quiescent

  • dormant

Why Dormancy Occurs

• Strong immune pressure forces bacteria into dormancy.

• Conditions inside granulomas include:

  • low oxygen

  • low nutrients

  • immune attack

18. Persistence, Dormancy and Latency

Persistence

• Broad term meaning long-term survival despite hostile conditions.

Dormancy

• Extreme reduction in metabolic activity.

Latency

• Clinically asymptomatic infection with potential for reactivation.

19. Evidence for Long-Term TB Latency

• A famous study compared TB strains isolated from a father in 1961 and his son in 1994.

• DNA fingerprinting showed identical strains.

• This suggested the son carried latent TB for decades before reactivation.

20. Bacterial Factors Important in TB Latency

Lipid Metabolism

• Latent TB bacteria may rely on host lipids for survival.

Glyoxylate Shunt & Gluconeogenesis

• Important metabolic pathways during dormancy.

dosR-dosS Regulon

• Important two-component regulatory system.

• Activated during hypoxia.

• Controls adaptation to low oxygen conditions.

Stringent Response

• Mediated by signalling molecules such as ppGpp.

• Helps bacteria survive starvation and stress.

21. Triggers for TB Reactivation

HIV Infection

• Most important risk factor.

• Weakens immune control of TB.

Other Immunosuppressive Conditions

• immunosuppressive therapy

• ageing

• chronic disease

Resuscitation Factors

• TB expresses resuscitation-promoting factors (Rpfs).

• These may help dormant bacteria resume growth.

22. Comparison Between Viral and Bacterial Latency

Potential Viva Questions & Answers

Question 1

“What is latency and why do pathogens enter a latent state?”

Answer

• Latency is an asymptomatic infection in which the pathogen remains inside the host without causing active disease.

• The infectious agent is still present and can reactivate later.

• Pathogens enter latency to avoid immune detection and survive long term inside the host.

• During latency, metabolic activity and gene expression are reduced.

• This allows pathogens to persist until conditions become favourable for reactivation and replication.

Question 2

“Explain latency in herpes viruses.”

Answer

• Herpes viruses infect epithelial cells during active infection and produce infectious virions.

• They then establish latency inside peripheral neurons.

• During latency, viral replication genes are silenced and no infectious particles are produced.

• The viral genome persists inside neurons for life.

• Latency-associated transcripts and viral microRNAs help maintain latency.

• Reactivation can occur during stress, trauma or immunosuppression, causing recurrent disease such as shingles.

Question 3

“Describe latent tuberculosis infection.”

Answer

• Latent tuberculosis infection occurs when Mycobacterium tuberculosis persists inside the body without causing active disease.

• Patients are asymptomatic and not infectious.

• The bacteria survive inside granulomas in a dormant, metabolically inactive state.

• Low oxygen and immune pressure contribute to dormancy.

• Latent TB can reactivate later, especially during HIV infection or immunosuppression.

• Important bacterial systems involved include the dosR-dosS regulon and the stringent response.

Question 4

“Compare bacterial and viral latency.”

Answer

• Viral latency involves persistence of the viral genome inside host cells without producing infectious particles.

• Bacterial latency involves survival of whole bacteria in a metabolically inactive state.

• Viral latency commonly occurs inside neurons, while bacterial latency such as TB occurs inside granulomas.

• Both strategies help pathogens avoid immune clearance and persist long term.

• Reactivation of both viral and bacterial latency is often associated with stress or weakened immunity.