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Innately Immune

2 September 2021 by Gertrud U. Rey

by Gertrud U. Rey

It is still not entirely clear why children are less susceptible to severe COVID-19. Early hypotheses included the possibility that children may have a stronger innate immune response, which is the response that occurs upon an initial encounter with a pathogen. Results from a recent study support this hypothesis.

To clarify why children have an enhanced ability to control a SARS-CoV-2 infection, the authors of the study collected nasal samples from SARS-CoV-2-negative and SARS-CoV-2-positive children and adults ranging in age from 4 weeks to 77 years. The presence of viral RNA in samples from SARS-CoV-2-positive participants was confirmed by PCR. The samples were also analyzed for the presence of different cell types using single cell RNA sequencing, a method that reveals the RNA expression profiles of individual cells. The authors detected 33 different cell types in the upper respiratory tract of all tested individuals, including 21 immune and 12 epithelial cell subtypes. The differences in the cell compositions of children and adults were quite dramatic – while nasal samples from healthy adults rarely contained immune cells, samples from children contained high levels of almost every immune cell subset, with neutrophils representing a substantial portion of the cell population. Neutrophils are an essential part of the innate immune system because they accumulate quickly at a site of infection, where they ingest pathogens and recruit and activate other immune cells.

Despite this difference in cell composition in the nasal mucosa of children and adults, the expression level of ACE2 (the SARS-CoV-2 binding target), was similar in both age groups. This result is contrary to previous suggestions that children may express less ACE2, but it is consistent with reports indicating that the frequency of SARS-CoV-2 infection in children is similar to that of adults.

Sentinel cells of the innate immune system recognize invading pathogens by sensing structurally conserved molecular motifs in infectious microbes. This sensing occurs through various pattern recognition receptors on or in the immune cells present in most tissues, like the well-characterized RIG-I-like receptors. Together with two other proteins, MDA5 and LGP2, RIG-I-like receptors detect the presence of viral RNA inside our cells and trigger a cascade of events that mobilize immune cells such as macrophages, neutrophils, and dendritic cells to the site of infection. Once there, these immune cells produce pro-inflammatory signaling proteins known as cytokines, which then cue other responses and prime adaptive T and B cells for future functions. Sensing of viral RNA by RIG-I and MDA5 initiates the production of a cytokine called interferon, a signaling protein that triggers downstream protective defenses.

When the authors compared the baseline expression of RIG-I-, MDA5-, and LGP2-encoding genes in the upper respiratory tract epithelial cells of healthy children and adults, they found that healthy children expressed significantly higher levels of these genes compared to healthy adults and SARS-CoV-2-positive adults who were in the early phase of infection. Samples from healthy children also contained a subpopulation of cytotoxic T cells that was absent in adults, and these T cells produced high levels of interferon gamma, a cytokine that inhibits viral replication and induces macrophages to engulf and digest pathogens.

When children became infected with SARS-CoV-2, they produced significantly higher levels of interferon gamma compared to SARS-CoV-2-positive adults, both in the early and later phases of infection. This observation is particularly interesting when considering that impaired interferon responses are a hallmark of severe COVID-19 and that SARS-CoV-2 is highly susceptible to interferon treatment. Furthermore, samples from SARS-CoV-2-infected children contained a subpopulation of SARS-CoV-2-specific memory T cells that was nearly absent in adults, suggesting that children might have an increased ability to respond to future SARS-CoV-2 reinfections. 

The increased numbers of innate immune cells and increased expression of pattern recognition receptor genes in the upper airways of children may facilitate a more efficient innate response to SARS-CoV-2 infection, leading to reduced viral replication and faster clearance of virus. This type of innate immune response seems to be delayed in older adults, and in an effort to “catch up,” may result in excessive inflammation, thereby ultimately causing more severe damage. Although there are likely more factors at play, this study brings us one step closer to understanding why COVID-19 is generally less severe in children.

Filed Under: Basic virology, Gertrud Rey Tagged With: ACE2, children, COVID-19, cytokine, innate immune response, innate immunity, innate sensor, interferon gamma, MDA5, memory T cells, neutrophil, RIG-I, SARS-CoV-2

The role of children in transmission of SARS-CoV-2

2 July 2020 by Gertrud U. Rey

by Gertrud U. Rey

It is well established that children experience less severe disease after infection with SARS-CoV-2. However, to what extent infected children contribute to transmission of the virus is less clear. This topic is of great interest as we prepare for the start of a new school year. 

Are children less susceptible to infection with SARS-CoV-2 or are they just less likely to develop clinical symptoms? Do infected children produce as much virus as infected adults? How likely are asymptomatically infected children to transmit the virus to others? The answers to these questions are inconsistent and confusing, for at least a couple of reasons. At this time it is difficult to directly measure these variables because most schools have been closed for the better part of the pandemic and children have been isolated from others. Also, children are often missed as index (first identified) cases in groups of related cases because they are more likely to be asymptomatic. To assess transmission from children to adults, many scientists have turned to statistical models. 

The authors of one such published statistical study applied data from China, Japan, Italy, Singapore, South Korea, and Canada to three different variants of a mathematical model to analyze age-dependent effects on transmission of SARS-CoV-2. A first variant of the model assumed that susceptibility to infection varies by age – with susceptibility being the probability of infection on contact with an infected person; a second variant assumed that the likelihood of developing clinical symptoms varies by age; and a third variant assumed that neither susceptibility nor clinical disease depend on age. The authors conclude that people under the age of 20 are half as susceptible to infection as those over 20, and that interventions aimed at children have at most a 20% impact on reducing SARS-CoV-2 transmission.

Another modeling study (a preprint, not yet peer-reviewed) out of Israel suggests that children are slightly less than half as susceptible to infection as adults, while their infectivity is 85% relative to that of adults. Infectivity is the probability that an individual can become infected within a certain time frame when making contact with another, identically susceptible individual. The authors conclude that children are less likely to become infected with SARS-CoV-2 than adults and that the chances of infection increase with age. 

A preprint out of France suggests that while high school students are as likely as adults to transmit the virus to others, children aged 6-11 are much less likely to do so. The authors show that three separate introductions of virus into three different elementary schools resulted in no further transmission of virus to other students or staff; consistent with results from Australia, Ireland, and a different French study.

However, these findings do not align with results from inquiries assessing viral load in children. After analyzing 3,303 COVID-19 patient sputum samples using two different PCR systems, German virologist Christian Drosten determined that children under the age of 19 produce virtually the same average levels of viral RNA as adults. Drosten argues that studies showing lower viral RNA levels in children relative to adults are subject to sampling bias because children are less likely to have symptoms and are therefore unlikely to be tested early in infection when virus levels in the nasopharynx are high. Instead, children are usually tested as contacts of index cases in symptom-triggered household studies, meaning that samples from children are obtained later in infection when virus levels in the nasopharynx are reduced. One way of validating this argument would be by analyzing children’s stool samples.    

Consistent with this suggestion, a recent report in Emerging Infectious Diseases suggests that both mildly symptomatic and asymptomatic children have high levels of viral RNA in the nose and saliva early during infection, but that these levels decline drastically within 1-2 weeks. In contrast, viral RNA levels in the feces remain high for more than three weeks after onset of symptoms. 

The data on transmission of SARS-CoV-2 from school-aged children to adults are limited because most schools have been closed since March. However, many child care centers in the US have remained open throughout the pandemic to care for the children of frontline workers and there have been no recorded coronavirus outbreaks directly linked to these facilities. Similar reports from Iceland, where extensive testing and contact tracing were implemented early during the pandemic, reveal only two documented cases of child-to-parent transmission, even though elementary schools and day care centers remained operational. 

School closures are a key intervention during epidemics of respiratory infections, and decisions surrounding the re-opening of schools this fall are fraught with uncertainty. While asymptomatically infected children are less likely to spread virus by coughing, and children have a smaller exhaled air volume than adults, they do engage in closer social contact with each other and are more physically active than adults. They are also more likely to put things in their mouths and share items. On the other hand, lengthy school closures have a negative impact on academic achievement and tend to increase educational inequalities because children of lesser means have less parental support and reduced access to resources for home learning. Only time will tell how school openings will affect the course of the pandemic. In the meantime, weekly testing of all students, followed by contact tracing and isolation of infected students and their contacts would be advisable.

Filed Under: Basic virology, Gertrud Rey Tagged With: children, COVID-19, SARS-CoV-2, school., transmission, viral, virology, virus, viruses

Microbiology books for kids

25 June 2010 by Vincent Racaniello

On TWiV 87 a listener asked us to recommend suitable books for children about microbiology. I have since asked for suggestions on Twitter and Facebook, and have begun to compile the following list.

  • The Invisible ABC’s by Rodney P. Anderson
  • The Magic School Bus #6: The Giant Germ by Anne Capeci
  • A World in a Drop of Water by Alvin and Virginia Silverstein
  • The Usborne Complete Book of the Microscope by Kirsteen Rogers
  • Jig, Jiggle, Sneeze by Joy Vitalis
  • Germs Make Me Sick! by Melvin Berger
  • Germ Stories by (Nobel prize winner) Arthur Kornberg (reviewed)
  • Invisible Allies: Microbes that shape our lives by Jeanette Farrell
  • Five Kids & A Monkey Investigate a Vicious Virus by Beth L. Blair
  • DNA is Here to Stay by Fran Balkwill

If you know of good microbiology books for children (ages 5-teen) please add them to the comments section, or email them to virology@virology.ws and I’ll add them to this list.

Update: Thanks to the readers who have sent in their suggestions. They are listed above in the order in which I received them.

Filed Under: Information Tagged With: book, children, education, kids, microbiology

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by Vincent Racaniello

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