Severity of Acute Infectious Mononucleosis Correlates with Cross-Reactive Influenza CD8 T-Cell Receptor Repertoires Nuray Aslan et al 2017

http://mbio.asm.org/content/8/6/e01841-17

Severity of Acute Infectious Mononucleosis Correlates with Cross-Reactive Influenza CD8 T-Cell Receptor Repertoires

1. Nuray Aslana,
2. Levi B. Watkina,
3. Anna Gila,
4. Rabinarayan Mishraa,
5. Fransenio G. Clarka,d,
6. Raymond M. Welsha,
7. Dario Ghersib,
8. Katherine Luzuriagac,d,
9. Liisa K. Selina,d

1. Jack R. Bennink, Editor

+Author Affiliations

1. liisa.selin@umassmed.edu.

ABSTRACT

Fifty years after the discovery of Epstein-Barr virus (EBV), it remains unclear how primary infection with this virus leads to massive CD8 T-cell expansion and acute infectious mononucleosis (AIM) in young adults.

AIM can vary greatly in severity, from a mild transient influenza-like illness to a prolonged severe syndrome.

We questioned whether expansion of a unique HLA-A2.01-restricted, cross-reactive CD8 T-cell response between influenza virus A-M158 (IAV-M1) and EBV BMLF1280(EBV-BM) could modulate the immune response to EBV and play a role in determining the severity of AIM in 32 college students.

Only ex vivo total IAV-M1 and IAV-M1+EBV-BM cross-reactive tetramer+ frequencies directly correlated with AIM severity and were predictive of severe disease.

Expansion of specific cross-reactive memory IAV-M1 T-cell receptor (TCR) Vβ repertoires correlated with levels of disease severity.

There were unique profiles of qualitatively different functional responses in the cross-reactive and EBV-specific CD8 T-cell responses in each of the three groups studied, severe-AIM patients, mild-AIM patients, and seropositive persistently EBV-infected healthy donors, that may result from differences in TCR repertoire use. I

AV-M1 tetramer+ cells were functionally cross-reactive in short-term cultures, were associated with the highest disease severity in AIM, and displayed enhanced production of gamma interferon, a cytokine that greatly amplifies immune responses, thus frequently contributing to induction of immunopathology.

Altogether, these data link heterologous immunity via CD8 T-cell cross-reactivity to CD8 T-cell repertoire selection, function, and resultant disease severity in a common and important human infection.

In particular, it highlights for the first time a direct link between the TCR repertoire with pathogenesis and the diversity of outcomes upon pathogen encounter.

IMPORTANCE

The pathogenic impact of immune responses that by chance cross-react to unrelated viruses has not been established in human infections.

Here, we demonstrate that the severity of acute infectious mononucleosis (AIM), an Epstein-Barr virus (EBV)-induced disease prevalent in young adults but not children, is associated with increased frequencies of T cells cross-reactive to EBV and the commonly acquired influenza A virus (IAV).

The T-cell receptor (TCR) repertoire and functions of these cross-reactive T cells differed between mild- and severe-AIM patients, most likely because these two groups of patients had selected different memory TCR repertoires in response to IAV infections encountered earlier.

This heterologous immunity may explain variability in disease outcome and why young adults with more-developed IAV-specific memory T-cell pools have more-severe disease than children, who have less-developed memory pools.

This study provides a new framework for understanding the role of heterologous immunity in human health and disease and highlights an important developing field examining the role of T-cell repertoires in the mediation of immunopathology.

KEYWORDS

• CD8
  
• Epstein-Barr virus
  
• TCR repertoire
  
• cross-reactive
  
• heterologous immunity
• immune memory
  
• influenza

FOOTNOTES

• Citation Aslan N, Watkin LB, Gil A, Mishra R, Clark FG, Welsh RM, Ghersi D, Luzuriaga K, Selin LK. 2017. Severity of acute infectious mononucleosis correlates with cross-reactive influenza CD8 T-cell receptor repertoires. mBio 8:e01841-17. https://doi.org/10.1128/mBio.01841-17.
  

 

Researchers connect severity of 'kissing disease' to T-cell population
Date:
December 5, 2017

Source:
American Society for Microbiology

Summary:
Acute infectious mononucleosis (AIM), also known as mono or the 'kissing disease,' is caused by the Epstein-Barr Virus (EBV). In a new paper, researchers connect the onset and severity of mono to T-cells that react to both EBV and the influenza A virus, which causes the flu. The study represents one of the first reported links between how a person's immune system responds to infection and receptors on T-cells, which instigate the immune response.

continues: www.sciencedaily.com/releases/2017/12/171205104219.htm

 

Health Psychol Behav Med. 2014 Jan 1;2(1):41-51.
Predictors of Post-Infectious Chronic Fatigue Syndrome in Adolescents.
Jason LA1, Katz BZ2, Shiraishi Y3, Mears CJ4, Im Y5, Taylor R6.
Author information

Abstract
This study focused on identifying risk factors for adolescent post-infectious chronic fatigue syndrome (CFS), utilizing a prospective, nested case-control longitudinal design in which over 300 teenagers with Infectious Mononucleosis (IM) were identified through primary care sites and followed. Baseline variables that were gathered several months following IM, included autonomic symptoms, days in bed since IM, perceived stress, stressful life events, family stress, difficulty functioning and attending school, family stress and psychiatric disorders. A number of variables were predictors of post-infectious CFS at 6 months; however, when autonomic symptoms were used as a control variable, only days spent in bed since mono was a significant predictor. Step-wise logistic regression findings indicated that baseline autonomic symptoms as well as days spent in bed since mono, which reflect the severity of illness, were the only significant predictors of those who met CFS criteria at 6 months.

KEYWORDS:
autonomic symptoms; chronic fatigue syndrome; longitudinal; mononucleosis; risk factors

PMID:

24660116

PMCID:

PMC3956649

 

CDC-funded study:

BMJ. 2006 Sep 16;333(7568):575. Epub 2006 Sep 1.
Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study.
Hickie I1, Davenport T, Wakefield D, Vollmer-Conna U, Cameron B, Vernon SD, Reeves WC, Lloyd A; Dubbo Infection Outcomes Study Group.
Author information

Abstract
OBJECTIVE:
To delineate the risk factors, symptom patterns, and longitudinal course of prolonged illnesses after a variety of acute infections.

DESIGN:
Prospective cohort study following patients from the time of acute infection with Epstein-Barr virus (glandular fever), Coxiella burnetii (Q fever), or Ross River virus (epidemic polyarthritis).

SETTING:
The region surrounding the township of Dubbo in rural Australia, encompassing a 200 km geographical radius and 104,400 residents.

PARTICIPANTS:
253 patients enrolled and followed at regular intervals over 12 months by self report, structured interview, and clinical assessment.

OUTCOME MEASURES:
Detailed medical, psychiatric, and laboratory evaluations at six months to apply diagnostic criteria for chronic fatigue syndrome. Premorbid and intercurrent illness characteristics recorded to define risk factors for chronic fatigue syndrome. Self reported illness phenotypes compared between infective groups.

RESULTS:
Prolonged illness characterised by disabling fatigue, musculoskeletal pain, neurocognitive difficulties, and mood disturbance was evident in 29 (12%) of 253 participants at six months, of whom 28 (11%) met the diagnostic criteria for chronic fatigue syndrome. This post-infective fatigue syndrome phenotype was stereotyped and occurred at a similar incidence after each infection. The syndrome was predicted largely by the severity of the acute illness rather than by demographic, psychological, or microbiological factors.

CONCLUSIONS:
A relatively uniform post-infective fatigue syndrome persists in a significant minority of patients for six months or more after clinical infection with several different viral and non-viral micro-organisms. Post-infective fatigue syndrome is a valid illness model for investigating one pathophysiological pathway to chronic fatigue syndrome.

PMID:

16950834

PMCID:

PMC1569956

DOI:

10.1136/bmj.38933.585764.AE
[Indexed for MEDLINE]

 

While posting related papers, I'm afraid I I just saw this Moss-Morris review was recently given a prize place on wikipedia's CFS entry:

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https://www.ncbi.nlm.nih.gov/pubmed/28712416