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.

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.

PubMed Link

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.

PubMed Link

African-Lineage Zika Virus Replication Dynamics and Maternal-Fetal Interface Infection in Pregnant Rhesus Macaques.

Crooks, et al. J Virol. 2021

In the study of Zika virus, African-lineage isolates have been under-prioritized in favor of Asian-lineage Zika virus. Therefore, the pathogenesis of African-lineage Zika virus is not rigorously characterized in translational model systems during pregnancy. To compare the two lineages, we infect pregnant rhesus macaques with either a control, Asian, or African-lineage Zika virus and assess disease progression. Our findings suggest that ZIKV of any genetic lineage poses a threat to pregnant individuals and their infants.

PubMed Link

Previous exposure to dengue virus is associated with increased Zika virus burden at the maternal-fetal interface in rhesus macaques.

Crooks, et al. PLoS NTD. 2021.

Concerns have arisen that pre-existing immunity to dengue virus (DENV) could enhance Zika virus (ZIKV) disease, due to the homology between ZIKV and DENV and the observation of antibody-dependent enhancement (ADE) among DENV serotypes. Here we show that macaques with a prior DENV-2 exposure had a higher burden of ZIKV vRNA in maternal-fetal interface tissues as compared to DENV-naive macaques. However, there were no other protective or enhancing effects observed in macaques with previous DENV exposure.

PubMed Link

Rapid evolution of enhanced Zika virus virulence during direct vertebrate transmission chains.

Riemersma, et al. J Virol. 2021

We use experimental evolution to model chains of direct and indirect Zika virus transmission by serially passaging a synthetic swarm of molecularly barcoded Zika virus within and between mosquitoes and mice. We observe that mouse-to-mouse transmission chains facilitated a rapid increase in virus replication and enhanced virulence in mice. These findings demonstrate that Zika virus is capable of rapid adaptation to a vertebrate host and indicate that direct human-to-human transmission could pose a greater threat to public health than currently realized.

PubMed Link

Revealing fine-scale spatiotemporal differences in SARS-CoV-2 introduction and spread.

Moreno, Braun, Riemersma et al. Nat Comms. 2020

In spring 2020, Milwaukee County had over 20-fold higher rates of SARS-CoV-2 infection per capita than did nearby Dane County, where Madison is located. We use genomic epidemiology to reveal dramatic differences in the patterns of SARS-CoV-2 introduction and spread. Our data also suggest that Wisconsin’s Safer at Home order reduced SARS-CoV-2 transmission. We speculate that demographic, socioeconomic, and other human factors account for much of the difference in virus spread in Milwaukee vs. Dane Counties.

PubMed link

Using virus sequencing to determine source of SARS-CoV-2 transmission for healthcare worker.

Safdar et al. Emerg Infect Dis. 2020

We have been applying molecular epidemiology to determine whether healthcare workers who become infected with SARS-CoV-2 were likely infected in a professional setting or in the community outside the hospital. This case report shows that a healthcare worker appeared to acquire SARS-CoV-2 in the community and not through treatment of known positive patients.

PubMed link

Molecularly barcoded Zika virus libraries to probe in vivo evolutionary dynamics.

Aliota et al. PLoS Pathog. 2018

A collaborative study in which we constructed libraries of Zika viruses bearing randomized silent mutations (molecular barcodes) to define how viral diversity changes with time during infection.

PubMed link

Infection via mosquito bite alters Zika virus tissue tropism and replication kinetics in rhesus macaques.

Dudley et al. Nat Commun. 2017

Here we show that infected mosquitoes can deliver Zika virus to macaque monkeys. Mosquito infection delayed the time to peak virus load and was associated with dramatic changes in Zika virus genetic diversity in infected monkeys. Mosquito infection is tractable in the laboratory and may slow the pace of Zika evolution.

PubMed link

Oropharyngeal mucosal transmission of Zika virus in rhesus macaques.

Newman et al. Nat Commun. 2017

Human case reports suggest that Zika virus could, in certain circumstances, be transmitted by kissing or other contact. We used a nonhuman primate model to show that transmission via oral exposure is theoretically possible, but likely requires a high dose of virus that is not found in body fluids of most Zika-infected individuals.

PubMed link

Deep Sequencing Reveals Potential Antigenic Variants at Low Frequencies in Influenza A Virus-Infected Humans.

Dinis, Florek et al. J Virol. 2016

Using Illumina deep sequencing, we examined the genetic diversity of influenza viruses infecting individual humans. We found some mutants with the potential to escape from antibody responses, but these were always present at low frequency and there was no evidence that natural selection was acting to increase their frequency. This study suggests that beneficial influenza virus variants are not efficiently selected over the course of a single human infection.

PubMed link

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.

PubMed Link

Viral Sequencing to Investigate Sources of SARS-CoV-2 Infection in US Healthcare Personnel.

Braun, Moreno, et al. Clin Infect Dis. 2021

In this study, we use viral genomics and limited epidemiological data to investigate the likely source of SARS-CoV-2 infection in health care workers at a major academic medical institution between 25 March and 27 December 2020. We find the majority of infections evaluated showed genetic similarity to viruses circulating concurrently in the community and showed no evidence for health-care related transmission. This emphasizes the ongoing importance of mask-wearing, physical distancing, robust testing programs, and rapid distribution of vaccines.

PubMed Link

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.

PubMed link

Quantifying within-host diversity of H5N1 influenza viruses in humans and poultry in Cambodia.

Moncla et al. PLoS Pathog. 2020

Avian influenza viruses pose a pandemic threat, and it is critical to understand their evolutionary potential in humans. Here we characterize H5N1 avian influenza viruses infecting humans and poultry in Cambodia. Our data show that H5N1 viruses generate putative human-adapting mutations during natural spillover infection, many of which are detected at >5% frequency within-host. However, short infection times, genetic drift, and purifying selection likely restrict their ability to evolve extensively during a single infection.

PubMed link

Diversity of Influenza A(H5N1) Viruses in Infected Humans, Northern Vietnam, 2004-2010.

Imai et al. Emerg Infect Dis. 2018

We define genetic and phenotypic diversity of H5N1 avian influenza viruses infecting humans. Surprisingly, although we detect within-host diversity, there is little evidence for adaptation to humans during a single spillover infection.

PubMed link

An updated influenza A(H3N2) vaccine generates limited antibody responses to previously encountered antigens in children.

Florek et al. Vaccine. 2018

It has been proposed that vaccines containing antigenically novel influenza strains can also boost responses to previously circulating strains. Here we show that this “back boost” effect is weak in children, who have limited influenza exposure histories.

PubMed link

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.

PubMed link

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.

PubMed link