Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated
host response to infection (1). Most recent estimations suggest that sepsis affects
about 49 million people and accounts for around 11 million deaths each year worldwide
(2), making it one of the leading causes of preventable death in all age groups. Sepsis
is a health priority according to the World Health organization (3), which provided
recommendations to improve the prevention, diagnosis and management of sepsis. Although
sepsis mortality has decreased over the past two decades (4, 5), the incidence of
sepsis continues to rise due to a higher number of patients with complex conditions
such as immunosuppression as well as an increase in more elderly people. A basic requirement
for effective sepsis management is timely and appropriate antimicrobial therapy (6,
7). With the increase of infections caused by multidrug resistant bacteria, the advances
made toward rapid multidrug testing to enable personalized antimicrobial therapies
is promising (Sun et al.). However, a major obstacle to improving sepsis outcomes
is the lack of knowledge on the intricate interplay between host defense, infection,
and pathogen virulence, as well as timing and nature of interventions. Over the past
decade, our understanding of sepsis has evolved from the earlier concept of sepsis
as a result of an excessive inflammatory response to the current notion that sepsis
outcomes are more likely related to the dynamic balance between pro-inflammatory and
counteracting anti-inflammatory mechanisms. To this end, animal models and a number
of human observational studies have paved the way toward precision trials on immunotherapy
for sepsis (Zijlstra et al.).
The aim of the Frontiers in Immunology Research Topic “The Immunology of Sepsis–Understanding
Host Susceptibility, Pathogenesis of Disease, and Avenues for Future Treatment” was
to collect state-of-the art articles and reviews on the role of the host immune system
affecting susceptibility, presentation, and outcome of sepsis. We hereby provide an
overview of this Frontiers in Immunology topic which includes 11 original articles,
13 review articles, 1 commentary, and 1 case report.
Susceptibility to Sepsis
Sepsis susceptibility may result from maturational, genetic, or acquired alterations
of the immune system. The incidence of sepsis is highest in newborns (8), and an increasing
body of studies characterize distinct patterns of immune responses in this age group
compared to children and adults. Schneider et al. for example, demonstrate that neonatal
macrophages express substantially less tumor necrosis factor compared to adult cells,
regulated through the transcription factor interferon regulatory factor 5 (IRF5).
Considering how few patients develop sepsis in comparison to the exposed population,
there is biological plausibility and epidemiologic evidence for underlying genetic
mechanisms affecting susceptibility to sepsis (9, 10). These may affect both very
rare variants associated with extreme phenotypes (11) and common variants that may
be of relevance at the populational level (12). Deficiency in mannose-binding lectin
(MBL) emerged two decades ago as a promising candidate to investigate this hypothesis
(13). Although polymorphisms affecting MBL serum levels are common and the role of
complement in host defenses against bacterial infections is well known, previous reports
on the relevance of MBL deficiency in susceptibility to infection remained conflicting
(14). Using a well-phenotyped prospective intensive care unit cohort, Levy et al.,
genotyped 420 pediatric patients with influenza-associated organ dysfunction for variants
in the MBL2 gene expected to result in low serum MBL levels. No clear relationship
was observed between genetic variants and overall outcomes in the cohort, neither
in within-cohort, nor in trio or control analyses. Interestingly, and similar to a
previous study, low-MBL producing variants were more common in a subset of fatal cases
with methicillin-resistant Staphylococcus aureus (MRSA), but the relevance of this
finding remains to be confirmed in larger studies.
Host-Pathogen Interaction
Children are prone to severe infections caused by encapsulated bacteria such as Streptococcus
pneumoniae, Streptococcus agalactiae (Group B streptococcus, GBS), Neisseria meningitis
and Haemophilus influenzae. The polysaccharide capsule is a key bacterial virulence
factor hindering opsonophagocytosis and complement-mediated bacteriolysis. However,
it also represents an effective target for vaccine development. In his review, Sadarangani
describes the mechanisms of vaccine-induced protection and illustrates successful
examples of pneumococcal and meningococcal capsular conjugate vaccines, while challenges
remain in the development of effective vaccines against non-type b H. influenzae and
GBS that also carry polysaccharide capsules. The article by Kadhim et al., demonstrates
a novel potential drug candidate to block staphylococcus enterotoxin-induced organ
damage. Finally, Deng et al. investigate mechanisms of complement evasion in streptococcal
strains.
Very timely considering the current coronavirus disease 2019 (COVID-19) pandemic,
and giving credit to an often overlooked problem, Lin et al., provide a thorough overview
of the epidemiology and pathogenesis of viral sepsis with a focus on herpes simplex,
influenza, and dengue viruses, as well as entero- and parechoviruses. Recognition
of a viral origin of sepsis could allow targeted treatment and reduce the unnecessary
use of antibiotics.
Understanding the Dysregulated Host Response to Infection
While the concept of a “dysregulated host response to infection leading to organ dysfunction”
in sepsis is broadly accepted, our understanding of the underlying mechanisms remains
very limited. The contributions to this Frontiers topic shed light on a number of
pathways that are likely involved.
Previous studies have shown that a subgroup of septic children and adults reveal similar
patterns to patients with hemophagocytic lymphohistocytosis (HLH), or macrophage activation
syndrome (MAS) such as cytokine storm, hyperferritinemia, and multi-organ dysfunction.
This entity has been termed macrophage activation-like syndrome (MALS). Karakike et
al. provide an overview of the available evidence on this topic, while the results
of the first randomized clinical trials (RCTs) on MALS are eagerly awaited. Zarjou
et al. assessed the inhibitory role of myeloid ferritin heavy chain and ferritin light
chain in a mouse model on nuclear factor kappa-light-chain-enhancer of activated B
cells (NF-kB) activation, illustrating a potential immunomodulatory role of ferritin
light chain.
More recently, insight into pro- and anti-inflammatory responses to the exposure of
pathogen- and damage-associated molecular patterns (PAMPs and DAMPs) suggest a dynamic
and heterogenous process (15). A fascinating research area in this regard relates
to epigenetic processes affecting gene expression during sepsis. Cross et al. provide
an overview on the literature on this topic. They summarize the rapidly growing number
of mainly laboratory studies indicating that epigenetic mechanisms are thoroughly
perturbed during sepsis, and are related to endothelial dysfunction and immunosuppression.
These observations may open up new treatment options, such as drug interventions with
histone deacetylase inhibitors for which pre-clinical animal studies suggest a potential
benefit. It will be interesting to see whether candidate drugs progress to clinical
studies on immune modulation in sepsis in the coming decade. Another possible drug
approach that could support a more balanced immune response is the blocking of the
Src family of tyrosine kinases with dasatinib, a drug for the treatment of chronic
myeloid leukemia and acute lymphoblastic leukemia. Indeed, Gonçalves-de-Albuquerque
et al. report promising results of using dasatinib in a mouse model of polymicrobial
sepsis.
Several other proteins and cells represent both encouraging biomarkers and therapeutic
targets for future strategies to combat sepsis. For example, Schrijver et al. report
that myeloid-derived suppressor cells (MDSCs) are a heterogenous group of immature
cells that expand in a number of conditions including sepsis. MDSCs suppress immune
responses of different cell types in the early and late phases of sepsis, and pre-clinical
studies show distinct patterns of expansion of MDSC subpopulations Observational studies
have already reported an association between high proportions of blood MDSCs and poor
outcome in sepsis patients. In a mouse model, Bomans et al. have elucidated mechanisms
involved in the functional reprogramming of naïve bone marrow monocytes after sepsis,
which lead to a “memory” of the innate immune system.
Other articles submitted to this Research Topic illustrate a number of recent discoveries
of cells and pathways that contribute to the host response to sepsis. Yin et al.,
demonstrate that phosphatase regenerating liver 2 (PRL2) regulates the generation
of reactive oxygen species in macrophages and thereby contributes to bactericidal
activity. Sjaastad et al., assessed the response to polymicrobial sepsis using a mouse
model and observed features consistent with chronic immunoparalysis, measured by reduced
antigen-specific T cell-dependent B cell responses.
Although the intestinal system has not been commonly considered in organ dysfunction
scores (1), it represents an extraordinary body surface area containing a high density
of lymphatic tissues and immune cells. The regulation between the host immune system
and intestinal pathogens as well as bacterial translocation play a key role in the
dynamic processes during and after shock. Increasing our understanding of these events
may point to ways for secondary interventions, as summarized in the review by Haussner
et al., on the role of the intestinal mucosa during sepsis. Expanding from this work,
the importance of intestinal microbiota in sepsis is explored in the excellent review
by Haak et al. shedding light on the therapeutic potential of microbiome-modifying
strategies for prevention and treatment of sepsis and sepsis-related late mortality.
Biomarkers, Monitoring the Immune System, and the Future of Immunomodulation in Sepsis
The immune status of patients with sepsis is subject to rapid progression, and hyperinflammation
and immunoparalysis may change dynamically. The failures to characterize the predominant
immunological phenotype of sepsis patients coupled with considerable disease and patient
heterogeneity represent major obstacles to develop effective immunomodulation-based
trials. Peters van Ton et al. discuss the critical need for accurate monitoring of
associated immune dysregulation to select patients more likely to benefit from targeted
immunomodulatory interventions, and to facilitate enrolment in clinical studies toward
personalized medicine.
The initial response to infection includes activation of innate immunity through soluble
and cell-bound pattern recognition receptors. Porte et al. for example, review the
available evidence on the role of the long pentraxin 3 (PTX3) in sepsis, a molecule
with high homology with C-reactive protein. PTX3 binds to various microorganisms and
has protective effects against sepsis in animal models. In human studies, high blood
levels of PTX3 are associated with sepsis severity, suggesting a potential use as
a biomarker. Furthermore, Tipoe et al. performed a systematic review and meta-analysis
of plasminogen activator inhibitor-1 (PAI-1) in sepsis. PAI-1 level is increased in
patients, and may be used as a predictor of disease severity and all-cause mortality
in sepsis.
Low expression levels of human leukocyte antigen D related (HLA-DR) by CD14 leukocytes
are increasingly used as a marker of sepsis-induced immunosuppression. Tamulyte et
al. report on a prospective cohort assessing monocyte HLA-DR by a point-of-care test.
They demonstrate the principle feasibility of the approach, which may help to identify
patients with a higher risk of worse outcomes due to sepsis. Excitingly, the development
of novel assays for immune profiling patients with severe infections has made huge
progress and is anticipated to enable personalized medicine trials in the very near
future.
The most widely studied immunomodulatory drugs in sepsis are corticosteroids. A large
number of high quality RCTs in critically ill adults are available, as nicely reviewed
by Heming et al. The immunomodulatory effects of statins have been recognized for
some time. Braga Filho et al. used a mouse model of CLP to demonstrate the positive
impact on simvastatin on survival and immune modulation.
Conclusions
In summary, the knowledge on the pathophysiology of sepsis has expanded in recent
years. Many original and review article in this Research Topic describe experimental
and clinical studies pointing to new candidates for biomarkers and interventions,
which may ultimately pave the way toward personalized care for sepsis. The availability
of improved immunophenotyping approaches, coupled with a number of candidate drugs
currently under investigation is promising. The marked heterogeneity of sepsis advocates
for highly selective interventions, targeted at populations selected for patients
who are more likely to respond to, and to benefit from therapeutic interventions.
The success of this endeavor will depend on the capability to incorporate effective
strategies for patient selection and targeted treatment allocation. As a promising
sign, a number of consortia have recently been launched to advance personalized immunotherapy
in sepsis. As nicely discussed by Talisa et al. trials using adaptive enrichment and
response adaptive randomization may be best suited to tackle the challenges of developing
effective treatments for clinical practice. Recently, large international randomized,
embedded, multifactorial adaptive platform trials (originally developed in the field
of cancer clinical research) have been launched in infectious diseases and hopefully
will boost the efficiency and impact of sepsis research. These advances may motivate
further personalized medicine trials leading to sustainable outcome improvements for
this major killer disease.
Author Contributions
All authors contributed to the article and approved the submitted version.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial
or financial relationships that could be construed as a potential conflict of interest.