Recent and featured papers from TCF Lab.
For a complete listing of Friedrich Lab papers, please see Tom’s complete NCBI Bibliography.
You can view his Google Scholar profile here.
Weak selection and stochastic processes limit the emergence of antigenic variants during household transmission of influenza A viruses
Ries et al. PLOS Pathogens, 2026
Influenza viruses are constantly evolving to escape our immune defenses, but exactly how new viral variants emerge and spread from person to person has remained unclear. In this study, we analyzed influenza virus samples collected from infected children and their household contacts to track viral evolution during natural infections and transmission events. We found that most genetic changes that arise within an infected person are not passed on to others. Instead, chance events play a much larger role than natural selection during transmission, creating a strong bottleneck that limits the spread of new viral variants. These findings suggest that the emergence of influenza strains capable of escaping existing immunity is relatively rare during typical household transmission, providing important insight into how influenza viruses evolve and spread through human populations.
Persistent SARS-CoV-2 infection: significance and implications
Machkovech et al. The Lancet Infectious Diseases, 2024
In this paper, we address the significant clinical and public health challenges posed by persistent SARS-CoV-2 infections in a subset of individuals. First, we highlight that persistent infections often go unrecognized, potentially impacting a substantial number of people, particularly those who are immunocompromised. Second, the formation of tissue reservoirs (including in non-respiratory tissues) might underlie the pathophysiology of the persistent SARS-CoV-2 infection and require new strategies for diagnosis and treatment. Finally, we propose persistent SARS-CoV-2 replication, particularly in the setting of suboptimal immune responses, is a possible source of new, divergent virus variants that escape pre-existing immunity on the individual and population levels.
Wolbachia-mediated resistance to Zika virus infection in Aedes aegypti is dominated by diverse transcriptional regulation and weak evolutionary pressures
Boehm, Jaeger, Ries et al. PLoS Neglected Tropical Diseases, 2023
In this study, we explore the potential of Wolbachia-based vector control strategies to mitigate arbovirus transmission, with a particular focus on their impact on Zika virus (ZIKV) dynamics within Aedes aegypti mosquitoes. First, we demonstrate that the introduction of the wMel strain of Wolbachia into Ae. aegypti alters mosquito gene transcription in a multifactorial manner, yet no single transcriptional signature is clearly associated with Wolbachia-mediated pathogen blocking. Second, we assess the within-host evolutionary dynamics of ZIKV in Wolbachia-infected mosquitoes and find that, despite the virus’s ability to replicate in the presence of Wolbachia, its evolution is subject to weak purifying selection and loose anatomical bottlenecks, with no evidence of viral escape from restriction. Finally, given that Wolbachia does not entirely eliminate viral replication, our findings highlight the potential for arboviruses to adapt to pathogen blocking over time, underscoring the need for continued surveillance and mechanistic studies to fully elucidate the long-term efficacy of Wolbachia-based interventions.
Avian H7N9 influenza viruses are evolutionarily constrained by stochastic processes during replication and transmission in mammals
Braun, Haddock, Crooks, et al. Virus Evolution. 2023
In this study, we compare patterns of sequence evolution for H7N9 Avian Influenza Virus (AIV) and mammalian H1N1 viruses during replication and transmission in ferrets. We show that three main factors – purifying selection, stochasticity, and very narrow transmission bottlenecks – combine to severely constrain the ability of H7N9 AIV to effectively adapt to mammalian hosts in isolated, acute spillover events. We find rare evidence of natural selection favoring new or mammalian-adapting mutations within ferrets but no evidence of natural selection acting during transmission. We conclude that human-adapted H7N9 viruses are unlikely to emerge during typical spillover infections. Our findings are instead consistent with a model in which the emergence of a human-transmissible virus would be a rare and unpredictable, though highly consequential, “jackpot” event.
Influenza A virus undergoes compartmentalized replication in vivo dominated by stochastic bottlenecks
Amato, Haddock, et al. Nat Commun. 2022
In this study, we understand genetic bottlenecks, constraining viral diversity and adaptation during the transmission of influenza A viruses (IAV) between hosts. We created highly diverse IAV libraries bearing molecular barcodes on two gene segments, enabling high-resolution tracking and quantification of unique virus lineages within hosts. Here we show that IAV infection in lungs is characterized by multiple within-host bottlenecks that result in “islands” of infection in lung lobes. Bottleneck events and localized replication stochastically sample individual viruses from the upper respiratory tract or the trachea that become the dominant genotype in a particular lobe. These populations are shaped strongly by founder effects, with limited evidence for positive selection. The segregated sites of replication highlight the jackpot-style events that contribute to within-host influenza virus evolution and may account for low rates of intrahost adaptation.
Pathology and viral evolutionary dynamics in a hamster model of persistent SARS-CoV-2 infection
Wei and Kuroda et al. Communications biology, 2026
SARS-CoV-2 infections typically resolve within 1-2 weeks. In rare cases, however, infection can last a year or more, particularly in people who are immunocompromised. These persistent infections pose health risks to the individual, because they can be difficult to eliminate through treatment. But SARS-CoV-2 persistence may also be a key to understanding the evolution and emergence of novel variants of concern. Persistent infections allow SARS-CoV-2 to replicate for prolonged periods in the presence of weakened immune responses, which may allow the virus to accumulate mutations that allow it to escape immune detection.
Despite these concerns little is known about the mechanisms or dynamics of long-term replication. In this study we describe a model for persistent SARS-CoV-2 infection using transgenic Syrian hamsters lacking the IL-2 receptor gamma subunit. In these genetically modified hamsters, SARS-CoV-2 disseminated throughout the body within 2 weeks of infection, and viral titers remained high at 100 days after inoculation. This prolonged infection involved extensive viral genetic diversification, with some evidence for tissue-specific differences in mutation patterns. This model allows for investigation into within-host viral evolution and provides a system to study how long-term replication, particularly in tissue reservoirs, may contribute to viral diversification.
Acute SARS-CoV-2 infections harbor limited within-host diversity and transmit via tight transmission bottlenecks.
Braun, Moreno, et al. PLoS Path. 2021
Understanding how efficiently variants emerge and transmit among hosts over the short-term is critical for predicting the pace of long-term SARS-CoV-2 evolution. To characterize how within-host diversity is generated and propagated, we combine extensive laboratory and bioinformatic controls with metrics of within- and between-host diversity to a dataset of SARS-CoV-2 genomes from acutely-infected individuals. We find that within-host diversity is low and transmission bottlenecks are narrow, with very few viruses founding most infections. The low amount of variation that does accumulate within the host is typically lost during transmission.
Transmission of SARS-CoV-2 in cats imposes a narrow genetic bottleneck.
Braun, Moreno, et al. PLoS Path. 2021
Transmission between hosts imposes a genetic bottleneck on respiratory viruses. The number of genetically distinct viruses that are transferred between hosts in a typical bottleneck (the “bottleneck size”) may differ for different viruses and transmission routes. In a domestic cat model, we show that SARS-CoV-2 transmission between hosts appears to involve stringent bottlenecks, in which only a few viruses are transmitted. Narrow bottlenecks may constrain the pace of SARS-CoV-2 evolution.
Selective Bottlenecks Shape Evolutionary Pathways Taken during Mammalian Adaptation of a 1918-like Avian Influenza Virus.
Moncla et al. Cell Host Microbe. 2016
This study shows that transmission bottlenecks might become more selective and less random as avian influenza viruses adapt to airborne transmission in mammals. This suggests that natural selection could drive a kind of “phase transition” in avian flu host jumping, accelerating adaptation once beneficial variants randomly arise.
This paper is the cornerstone of one of our major current projects and was a featured article in Cell Host & Microbe.
Selection on haemagglutinin imposes a bottleneck during mammalian transmission of reassortant H5N1 influenza viruses.
Wilker, Dinis et al. Nat Commun. 2013
Here we show that natural selection on the hemagglutinin attachment protein drives genetic bottlenecks as H5N1 influenza viruses adapt to become transmissible between mammals. We further show that viral variants present frequencies as low as 6% in one host can be transmitted by respiratory droplet.
These findings established our interest in transmission bottlenecks and suggest that natural selection could effectively winnow low-frequency transmissible variants from within a viral population.