When meeting a new baby, we’ve all
gotten the advice to wash our hands first and avoid giving the baby a kiss to
prevent the spread of infectious diseases.
That advice is extremely important, as illnesses in babies can become
life-threatening quickly. Interestingly,
infants are able to fight off viral infections better than bacterial
infections. Only
1% of infants admitted to an intensive care unit suffer from viral infections (1), while
bacterial illnesses cause a majority of admissions to both neonatal (infant)
and pediatric intensive care units (2). Considering
this evidence, the investigators in this paper wanted to determine how babies are able to fight viruses
effectively.
A
little background:
As disease-causing organisms try
to establish an infection in a host, the host’s immune system mounts a response
to neutralize the threat. Initially, the
immune system recognizes that such a pathogen is present by using pattern
recognition receptors (PRRs). These
receptors bind to molecular signals present on a wide variety of pathogens,
called pathogen-associated molecular patterns (PAMPs). Each class of PRR recognizes PAMPs displayed
on a certain type of pathogen; this paper deals with toll-like receptors (TLRs)
and various PRRs that recognize viral genetic material already inside the host
cell. Within the TLR family, there are
various types that respond to different PAMPs (for a quick video explanation, follow this link!)
 |
| Figure 1. Examples of pattern recognition receptors (PRRs). (https://www.researchgate.net/figure/Pattern-recognition-receptors-and-their-cognate-ligands-TLRs-3-7-8-9-and-11-have-been_fig5_49763131) |
The innate response activated by
PAMPs binding to PRRs primes components of the later, more specific adaptive
response. For example, signaling through
PRRs that recognize viral nucleic acids in the host cell’s cytoplasm (cytosolic
nucleic acids, CNAs) initiates the production of antiviral molecules called
type I interferons (also known as interferon-α/
IFN-α and interferon-β/IFN-β). The CNA sensors activate a transcription
factor known as IRF3, which is necessary for interferon production. TLRs are also able to increase production of
interferons; however, they do so through a different pathway. TLRs that are bound to the exterior membrane
of the cell, like TLR4, have to move to an endosome before being able to
interact with TRAF3 to activate IRF3.
This process requires a protein called Rab11a, without which monocytes are unable to produce IFN in response to TLR4-signaling (3).
 |
| How TLRs and cytosolic nucleic acid sensors signal to IRF3 |
So
what does that mean for vaccines?
After the innate immune response has
been triggered, components of the specialized adaptive immune system respond to
aid in the fight against the pathogen. T cells are some of those special agents
who come to help, and they can be from a variety of different subgroups. One subgroup of T cells is Th1, which helps
the adaptive immune response fight pathogens like viruses and certain bacteria
that enter the cell. IFNs are required to promote a Th1-heavy
adaptive T cell response (4) and other important specialized responses (5). Since babies are so susceptible to bacterial
infections, Brennan et al. hypothesized that infants might not be able to trigger
an IFN response to intracellular bacteria. Promotion
of a Th1 response is one of the main goals of vaccine development (6), so adding a
component that helps vaccines set up such a response against bacteria might
work to better protect babies from bacterial infections.
TLRs, CNA sensors, and Interferons
To figure out whether infants are
capable of mounting an interferon response at all, the researchers stimulated monocytes (a type of immune cell) taken from cord
blood with various PAMPs and compared the response to that of monocytes derived
from adults. Neonatal monocytes produced
less IFN-α and -β in response
to PAMPs (LPS, CpG, and CL075) that stimulate TLRs than adult monocytes. In contrast, neonatal cells were able to
produce as much or more IFN as adult
cells when treated with viral nucleic acid mimics (Poly(I:C) and Poly(dA:dT)). This
means that monocytes from infants have the capability to make interferon; they
just don’t ramp up production in response to TLR activation. Because many immune cells make IFN, the
authors also verified that there were equal amounts of IFN-producing cells in
babies and adults.
 |
| Cord blood monocytes make less IFN than adult monocytes in response to LPS, but produce the same amount in response to cytosolic nucleic acids. (Brennan et al., 2018) |
Another immune system signaling molecule, tumor necrosis factor a (TNF-α), also promotes a Th1 response. Signaling pathways from PRRs to stimulate TNF-α production are different from those that produce IFNs; therefore, Brennan et al. wanted to investigate whether the TNF-α response to TLRs was also diminished in babies. They again stimulated monocytes from adults and infants with viral genetic material to trigger CNA sensors, while a different group of cells were treated with molecules that bind to TLRs. In response to viral nucleic acids like poly(I:C), cord blood monocytes produced more TNF-α than adult monocytes. This pattern was similar to the trend seen in IFN-α production. Unlike IFN-α, however, there was no difference between the quantities of TNF-α produced by neonates and adults in response to TLR activation. This finding suggests that babies’ TLRs are indeed functional because they are able to signal through the other pathway to produce appropriate amounts of TNF-α. Despite the intact TNF-α pathway, neonatal TLRs aren’t able to signal to the IFN-producing pathway.
 |
| Neonatal monocytes (CBMCs) produce more TNF-α in response to viral nucleic acid mimics (Poly(I:C), left) than adult monocytes; both cell types make the same amount in response to TLR stimulation (LPS, right). (Brennan et al., 2018) |
Once they established this baseline information, Brennan et al. wanted to figure out why neonatal monocytes make less IFN and the following consequences on the immune response. IRF3 is the transcription factor responsible for turning on production of IFN-a and -b, so the investigators measured the activation of IRF3 in cord blood monocytes responding to various PAMPs. IRF3 was greatly activated in response to viral nucleic acid mimic poly(I:C), but it was not as strongly activated in response to TLR stimulants LPS and CpG. This failure to increase IRF3 in response to TLR signaling agrees with the cord blood monocyte’s inability to produce adequate levels of IFN. IFN-α and -β release causes cells to start making proteins coded by genes known as interferon-stimulated genes (ISGs), and the researchers measured the protein levels of an ISG called CXCL10 to investigate the downstream effects of decreased IFN production. Though CNA sensor activation caused neonatal monocytes to produce the same levels of CXCL10 as adult monocytes, the neonatal cells produced less CXCL10 than adult cells did in response to TLR signaling.
Some TLRs have to locate to
endosomes to activate IRF3, but CNA sensors do not. Brennan et al. hypothesized
that neonatal TLRs might have trouble with moving TLRs to endosomes, which
would explain the decreased IRF3 activation.
As mentioned before, Rab11a helps activated TLR-4 move to
endosomes. In adult monocytes, Rab11a
levels are increased after TLR-4 activation and Rab11a is located close to TLR-4
molecules. On the other hand, cord blood
monocytes produce less Rab11a in
response to TLR-4 signaling and have fewer
Rab11a molecules close to TLR-4 molecules.
If TLR-4 doesn’t have Rab11a to help it get to the endosome, it can’t
activate IRF3 to make the cell produce IFN (which is what may be happening in
babies’ monocytes).
 |
| Cells from infants have less Rab11a (colored red) after TLR4 stimulation with LPS, which is important for TLR4 to activate IRF3. (Brennan et al., 2018) |
Because stimulation of the Th1-polarized adaptive response is important to effective vaccine development, the researchers tested whether there were differences in Th1-polarizing molecule production between adult and neonatal monocytes. Treatment with viral nucleic acid mimic poly(I:C) increased the production of IL-12p70 (a molecule that drives naïve T cells to become Th1 cells) more in neonatal monocytes than adult monocytes. This increased response was not observed in response to molecules that stimulate TLRs, further supporting the idea that neonates’ immune systems are optimized to respond to viruses. No differences between adult and neonatal cells were seen in autoimmune Th17 induction or anti-inflammatory interleukin-10 production.
So,
what’s the big deal? Vaccines!
The main take-away from Brennan et
al.’s research is that infants are able to mount a robust IFN response to
intracellular viral nucleic acids but not to TLR activation. This means that they are better able to fight
viruses that stimulate intracellular CNA sensors than pathogens that stimulate
TLRs, which agrees with the observed fewer ICU admissions for viral
infections. Since babies can respond so
well to viruses, vaccine developers might be able to harness this response to
produce a more effective vaccine. In
addition to the weakened or killed pathogen, vaccinations contain an adjuvant that helps generate an immune response to
ensure that the person will be able to fight the pathogen in the future. Currently, vaccines contain an adjuvant
called alum that is unable to generate Th1 responses in neonatal and pediatric
patients. Using a viral nucleic acid
mimic as an adjuvant might be a better option for generating the most effective
response against pathogens.
References
1- Verboon-Maciolek, M. A., Krediet, T.
G., Gerards, L. J., Fleer, A., & van Loon, T. M. (2005). Clinical and
epidemiologic characteristics of viral infections in a neonatal intensive care
unit during a 12-year period. The Pediatric Infectious Disease Journal, 24(10),
901–904. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/16220089
2-Wisplinghoff,
H., Seifert, H., Tallent, S. M., Bischoff, T., Wenzel, R. P., & Edmond, M.
B. (2003). Nosocomial bloodstream infections in pediatric patients in United
States hospitals: epidemiology, clinical features and susceptibilities. The
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4-Crouse,
J., Kalinke, U., & Oxenius, A. (2015). Regulation of antiviral T cell
responses by type I interferons. Nature Reviews Immunology, 15(4),
231–242. https://doi.org/10.1038/nri3806
5-Rizza, P., Moretti, F., Capone, I.,
& Belardelli, F. (2015). Role of type I interferon in inducing a protective
immune response: perspectives for clinical applications. Cytokine &
Growth Factor Reviews, 26(2), 195–201.
https://doi.org/10.1016/j.cytogfr.2014.10.002
6-Coffman,
R. L., Sher, A., & Seder, R. A. (2010). Vaccine adjuvants: putting innate
immunity to work. Immunity, 33(4), 492–503.
https://doi.org/10.1016/j.immuni.2010.10.002
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