The growing role of infectious disease genomics
Figure 1: Infectious disease genomics applications may be leveraged to characterize the pathogen (pathogen genomics), or host responses (host genomics), to inform the development of improved interventions and disease surveillance.
Managing infectious disease threats and controlling outbreaks is no easy task. Keeping up with rapidly diversifying pathogens and tracing disease epidemiology in an ever more connected world requires continuous research, surveillance, and global collaboration to successfully safeguard public health. Pathogens continually evolve and adapt to environmental changes, enabling them to evade host immune responses, and this diversification contributes to the emergence of new strains with altered virulence and/or resistance to existing treatments.
The genomics revolution has vastly improved our understanding and management of infectious diseases. Enabling researchers to query key pathogen characteristics with unprecedented resolution, infectious disease genomics unlocks vital information into how pathogens evolve, function and spread. Thanks to the higher throughput and capacity of sequencing technologies, genomics research today plays an increasing role in understanding, forecasting, and managing infectious diseases from the individual to population scale. It’s also central to the development of improved diagnostics and interventions, from vaccine design to drug repurposing.
There are numerous applications of genomics in the infectious diseases arena, with sequencing tools being harnessed to gain a better understanding of both pathogens and host organisms. In this blog, we highlight the growing role of genomics research in the monitoring and surveillance of infectious diseases, and how it is paving the way towards precision healthcare.
The diversification dilemma
One of the ever-present challenges faced by healthcare systems in infectious disease management, is the propensity of pathogenic viruses and bacteria to rapidly adapt and evolve through genetic mutations and recombination. Pathogen evolution is driven by the selective pressures imposed by the host’s immune responses, environmental conditions, and other factors.
The mutation of pathogens poses challenges for public health efforts, as it can complicate the development of effective vaccines and treatments. This diversification can give rise to new strains displaying altered pathogen factors and corresponding host targets, while stimulating novel host immune factors. These changes can alter the pathogen’s characteristics, such as its virulence, transmissibility, or ability to evade the host’s immune system .
Pathogen diversification is central to many of today’s most pressing infectious disease public health challenges, the rising burden of antimicrobial resistance being a prominent example. In light of the possibility for multiple virulent pathogen strains to coexist, continuous research and monitoring is key to informing the development of reliable interventions. Much of today’s infectious disease genomics research seeks to better understand the process of diversification and find strategies to harness this data for improved interventions and forecasting.
Viral pathogen diversification
Viral evolution is rapid thanks to high mutation rates, short replication cycles, selection pressures, and susceptibility to zoonotic events and recombination. As a result of these mechanisms, viral evolution drives the continuous generation of diverse viral populations, making the development of effective interventions a headache for developers. The challenges posed by viral diversification came to prominence during the COVID-19 pandemic, as the emergence of novel SARS-CoV-2 variants gave rise to epidemic waves .
Common mechanisms of viral evolution include antigenic drift and antigenic shift, which are both prominent mechanisms for influenza. Drift refers to small mutations that drive subtle changes to surface antigens. By incrementally altering their antigen proteins over time, viruses can begin to evade the host immune system. For this reason, flu vaccines need to be updated each year to keep up with the ever-evolving flu viruses.
Antigenic shift occurs less frequently but is a much more abrupt and dangerous phenomenon in which viruses display entirely new surface antigens. This often occurs with viruses of zoonotic origin. Antigenic shift is responsible for most flu pandemics, including the swine flu outbreak in 2009 .
Bacterial pathogen diversification
Like viruses, bacteria can also evolve and diversify to overcome environmental challenges and selection pressures. Bacteria undergo mutations during DNA replication like viruses, but given that bacteria have more complex cellular structures, there are some key differences, such as the ability of bacteria to perform more complex mechanisms of genetic exchange.
Bacteria are equipped to exchange genetic material through a variety of processes, including conjugation, transformation, and transduction. Furthermore, the ability of bacteria to form a monolayer or biofilm enables them to exchange genetic material more easily, through a shared extracellular matrix. The ability of bacteria to perform horizontal gene transfer allows for the rapid spread of genes, including those relating to antibiotic resistance, virulence factors, or metabolic advantages, contributing to bacterial diversification .
Antimicrobial resistance is the most pressing issue with regards to bacterial diversification. The misuse or overuse of antibiotics imposes strong selection pressures on bacterial populations. Bacteria that possess genes carrying resistance to antibiotics have a survival advantage that is then passed on to the next generation(s). As such, the widespread use of antibiotics has led to the emergence and spread of antibiotic-resistant strains, posing a significant public health threat.
Pathogen-focused infectious disease genomics
Gaining a deeper understanding of pathogens at the molecular level is a highly valuable application of next generation sequencing (NGS) technology. So-called pathogen genomics is being rapidly adopted by healthcare agencies worldwide to improve public health and disease monitoring.
Pathogen characterization and outbreak mapping
One of the most widely adopted sequencing technologies employed in pathogen genomics is whole genome sequencing (WGS). WGS has become a rapid and affordable approach that can sequence the entire genome of a virus (typically 7,000 – 20,000 base pairs) or bacterium (3-6 million bp) with unprecedented resolution, for as little as $200 . Sequence data can be compared computationally, revealing valuable insights into the evolutionary relationships between pathogens, as well as to predict key phenotypic characteristics, such as virulence, serotype, and antimicrobial resistance.
WGS is fast becoming the standard for characterizing foodborne disease outbreaks . Enabling rapid and accurate tracking of the sources and transmission routes of foodborne pathogens, WGS enhances the ability to map outbreaks and link cases to specific food products, restaurants, and production facilities, enabling timely interventions to prevent further spread of disease. It is particularly useful for segregating cases during multiple outbreaks of the same disease in parallel, for example, Salmonella.
NGS analysis of pathogenic DNA and RNA is widely leveraged to inform vaccine development. For example, the development of the seasonal influenza vaccine is a vast annual undertaking requiring international collaboration to reliably select candidate vaccine strains for the upcoming flu season. While this process once relied on tricky viral culture and sluggish Sanger sequencing, NGS now offers a substantially more rapid and informative approach.
NGS sequence data provides a high-resolution view of viral emergence and reveals deep insights into evolutionary history and trajectory to inform better vaccine decision making. NGS proved to be a keystone technology during the COVID-19 pandemic, enabling the vaccine development process, from pathogen discovery to approval, to be achieved in record time .
The rapid turnaround time and ever-increasing cost-effectiveness of NGS has enabled genomics technology to be used more and more for infectious disease diagnostics. While targeted sequencing approaches, such as amplicon-based or hybridization sequencing, allow for the specific detection of known pathogens or the monitoring of their evolution, metagenomic sequencing is a target-independent approach that allows for the unbiased detection of various pathogens, including viruses, bacteria, fungi, and parasites. This unbiased approach is particularly valuable in cases where the causative agent is unknown. Molecular diagnostic platforms are therefore becoming indispensable in the clinic .
In contrast to pathogen genomics, host genomics deals with the other side of the equation: the host organism’s response to infection. Individuals are found to respond differently when ill with the same disease, even when factors like exposure and comorbidities are comparable. Host genomics seeks to understand how genetic factors influence an individual’s susceptibility to infection, response to pathogens and overall prognosis. Analyzing the host’s genome in addition to the pathogen facilitates the development of more targeted and personalized strategies for disease prevention, treatment, and interventions.
The host genome plays a crucial role in determining an individual’s immune response, ability to resist infections, and susceptibility to specific pathogens. This became starkly apparent with the COVID-19 pandemic, during which some patients were asymptomatic, others experienced mild symptoms, and a percentage of the population experienced a severe, life-threatening illness requiring hospitalization and ventilation. In addition, some experienced an acute illness while some were susceptible to “Long COVID”, a chronic illness with long-lasting symptoms.
Transcriptome analysis of patients across the spectrum of responses to SARS-CoV-2 infection helped to reveal key differences in immune responses between patient groups. For example, the enrichment of plasma cells was characteristic of all COVID-19 patients, while enrichment of interferon and neutrophil gene signatures was found to be specific to patients requiring hospitalization. As such, transcriptomic analysis helped to reveal genetic signatures for the identification of the most at-risk groups.
The baricitinib success story
Host genomics made a significant clinical impact throughout the COVID-19 pandemic, and a great illustration of this is the drug repurposing success story of baricitinib. During a pandemic emergency, being able to repurpose drugs is invaluable, as these have already been through development and clinical approval, making for swift intervention, if an appropriate existing drug can be identified.
Tyrosine kinase 2 (TYK2) is a member of the Janus kinase (JAK) family of kinases, which regulate key signaling events during immune responses and autoimmune processes. Because of its key role in rheumatoid arthritis (RA), a JAK inhibitor drug, baricitinib, had been approved for use in RA patients. Genomic analysis of severe COVID-19 patients led to the discovery of TYK2 gene alterations in those with severe illness. As such, it was hypothesized that baricitinib could have clinical utility in the treatment of severe COVID-19, supported by bioinformatics and computational predictions .
The RECOVERY trial, which aimed to identify candidate drugs to repurpose for COVID-19 therapy, found that baricitinib significantly reduced mortality in those with severe COVID-19, leading to the drug being clinically approved for such use.
Turning the tide in the race against infectious diseases
We have seen just a few of the myriad ways in which genomics technologies are transforming our approach to infectious disease management. Based on a greater understanding of the genomics and transcriptomics of both the pathogen and host, genomics is at the forefront of supporting rapid and convenient vaccine development, more advanced diagnostics, patient risk stratification and personalized interventions.
At Eremid®, we support groundbreaking genomics research. From molecular diagnostic development to transcriptome analysis supported by a full suite of sequencing technologies, we can provide the technology and expertise to take your infectious disease genomics program to the next level.
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