New findings from NIEHS researchers could help clinicians diagnose and determine the likely course of diseases caused by respiratory syncytial virus (RSV) and other pathogens. The study was published Aug. 20 in the Journal of Clinical Investigation.

Some infants have severe responses to RSV infection and require hospitalization. The new study links a gene variant with an immune response that increases lung disturbance.

The research showed that a genetic variant that controls the effects of the well-known tumor suppressor p53 on immune responses is linked to disease severity in infants infected with RSV. According to the authors, the results could also guide immune-based treatment strategies for cancer.

Resnick holds a secondary appointment in the NIEHS Immunity, Inflammation and Disease Laboratory. (Photo courtesy of Steve McCaw)

“Beyond its classical function as guardian of the genome, the tumor suppressor protein p53 has recently been found to participate in other processes, including the immune response,” said senior study author Michael Resnick, Ph.D., head of the NIEHS Chromosome Stability Group. “Together with past research, our new findings support an extensive p53-immune axis in humans as a guardian of immune integrity.”

Innate immunity — good until it is bad

The human innate immune system provides early and effective responses against invading pathogens and potential environmental threats. Proteins called toll-like receptors, which are expressed in a variety of immune-sensing cells, are involved in the first line of defense against infections.

Although the innate immune response provides immediate protection, it is relatively nonspecific in its mode of attack on pathogens, so it can damage healthy tissue if it lasts too long.

Tumor suppressor influences immune system

Toll-like receptor 8 (TLR8) comes into play when the innate immune system responds to infection by single-stranded RNA viruses such as RSV (see sidebar). In a previous study, Resnick and his collaborators found that when p53 is turned on, expression of TLR8 can increase nearly three-fold in immune cells from some individuals.

Polack, an infectious disease specialist, is a long-time collaborator with Kleeberger. (Photo courtesy of Fernando Polack)

The ability to respond to p53 depends on a difference, called a single nucleotide polymorphism (SNP), in a specific DNA building block found in the control region of the TLR8 gene. Cells with that SNP have increased TLR8 gene expression in the presence of p53, unlike cells that lack the common variant.

Inflammation is the link

Menendez has worked at the NIEHS for more than 17 years, starting out as a visiting fellow before becoming a staff scientist. (Photo courtesy of Steve McCaw)

Because of the role of TLR8 in immune responses to RSV, the researchers wanted to know whether this SNP is associated with severity of RSV disease. In the new study, they examined a group of infants in Argentina who were hospitalized with RSV infection. This was made possible by a collaboration with study co-author Fernando Polack, M.D., executive director of Fundacion INFANT in Buenos Aires.

Data on the infants’ genotypes revealed that the p53-responsive genetic variant was associated with increased RSV disease severity, based on the need for supplemental oxygen and hospitalization.

The authors hypothesized that higher p53-induced TLR8 expression led to greater production of inflammatory molecules called cytokines. Although these molecules help facilitate pathogen control and clearance, they can also cause complications, such as increased lung disturbance.

The researchers conducted additional experiments in collaboration with the NIEHS Clinical Research Unit and the Environmental Polymorphisms Registry. The studies confirmed that p53 activation can greatly increase immune responses to single-stranded RNA in white blood cells from people with the p53-responsive variant.

“Taken together, the findings suggest that p53 can strongly influence TLR8-mediated immune responses,” said first author Daniel Menendez, Ph.D., staff scientist in Resnick’s group. “The results are consistent with our previous findings showing that p53 transcriptionally regulates several immune genes.”

Kleeberger’s research focuses on the role of genetic background in susceptibility to pulmonary effects of environmental stimuli. (Photo courtesy of Steve McCaw)

Broad clinical implications

In addition to RSV, the results may be relevant to other viral- and pathogen-associated diseases. For instance, TLR8 has been implicated in recognizing and initiating immune responses to Zika, HIV, and tuberculosis, the authors noted.

“Moreover, the findings could be clinically relevant for immune-based cancer therapies,” said Steven Kleeberger, Ph.D., head of the NIEHS Environmental Genetics Group. “For instance, p53-dependent activation of TLR8 might be employed to enhance tumor-directed immune responses.”

Citations:
Menendez D, Snipe J, Marzec J, Innes CL, Polack FP, Caballero M, Schurman SH, Kleeberger SR, Resnick MA. 2019. p53-responsive TLR8 SNP enhances human innate immune response to respiratory syncytial virus. J Clin Invest; doi: 10.1172/JCI128626 [Online 2019 Aug 20].

Menendez D, Shatz M, Azzam K, Garantziotis S, Fessler MB, Resnick MA. 2011. The toll-like receptor gene family is integrated into human DNA damage and p53 networks. PLoS Genet 7(3):e1001360.

Nguyen TT, Grimm SA, Bushel PR, Li J, Li Y, Bennett BD, Lavender CA, Ward JM, Fargo DC, Anderson CW, Li L, Resnick MA, Menendez D. 2018. Revealing a human p53 universe. Nucleic Acids Res 46(16):8153−8167.

(Janelle Weaver, Ph.D., is a contract writer for the NIEHS Office of Communications and Public Liaison.)