Chance and Necessity

If we free-associate the word “chance” you may arrive at “I’ll take my chances” before potentially arriving at Thomas Bayes’ “Doctrine of Chances”. Jacques Monod was an early explorer of the collision of probability and chance in biology.

THE PRINCE OF CHANCE

Jacques Monod grew up just down the coast from Monte Carlo in Cannes, France, another town famous for its casinos and, later, its film festival. Graced with movie star looks—one prominent French journalist described him as a “prince” who resembled Hollywood icon Henry Fonda, as well as considerable musical talent, and an exceptional intellect, Monod struggled to decide on a career path through his twenties. After distinguishing himself in the French Resistance, Monod rose to fame not as an actor or musician, but as a brilliant biologist. He shared the 1965 Nobel Prize in Physiology or Medicine for seminal discoveries about how genes work.

A pioneer in the field of molecular biology, Monod was privy to the blizzard of discoveries in the 1950s and early 1960s about the molecules that determined the characteristics of living things—what Monod and others dubbed “the secrets of life.” He kept close company with a relatively small international community of leading researchers. For example, when James Watson and Francis Crick cracked the structure of DNA (deoxyribonucleic acid) in 1953, Monod was one of the first with whom Watson shared the breakthrough.

But as a Frenchman steeped in his culture’s deep philosophical traditions, Monod was interested in science for more than just science’s sake. After the war, Monod befriended France’s leading philosopher-writer Albert Camus, and the two men pondered questions of human existence in Left Bank cafés. Monod felt that the public misunderstood the principal purpose of science as being the creation of technology. Rather, Monod believed technology was merely a by-product. He said, “the most important results of science have been to change the relationship of man to the universe, or the way he sees himself in the universe”—a relationship of equally intense interest to his friend Camus.

Monod thought that there were profound philosophical implications of the new molecular biology, particularly in the realm of heredity, which had gone largely unnoted in the broader culture. Several years after his Nobel Prize and Camus’ untimely death, he decided to write a book to try to bring the meaning of modern biology to laypersons.

“[T]he ‘secret of life’…has been laid bare,” he wrote.

“This, a considerable event, ought certainly to make itself strongly felt in contemporary thinking.”

Monod used several chapters to describe the insights that had very recently emerged from the study of DNA and the deciphering of the genetic code. He understood this knowledge would be unfamiliar to most readers, so he included an appendix with chemical structures of proteins and nucleic acids, and a primer on how the genetic code worked.

In a matter-of-fact style, he explained genetic mutations as accidental alterations—substitutions, additions, deletions, or rearrangements—in the text of DNA, in the sequence of the long strings of chemical bases (ACTTGATAA, etc.) that make up genes.

Then, almost without warning, he turned to the broader implications of how mutations arise in DNA. It is worth quoting him at length for after 111 pages of background, he delivered one of the most powerful ideas in five centuries of science (all italics are original):

“We call these events accidental; we say they are random occurrences. And since they constitute the only possible source of modifications in the genetic text, itself the sole repository of the organism’s hereditary structure, it necessarily follows that chance alone is at the source of every innovation, of all creation in the biosphere.

“Pure chance, absolutely free but blind, at the very root of the stupendous edifice of evolution: this central concept of modern biology is no longer one among other possible or even conceivable hypotheses. It is today the sole conceivable hypothesis, the only one that squares with observed and tested fact. And nothing warrants the supposition—or the hope—that on this score our position is likely ever to be revised.

“There is no scientific concept, in any of the sciences, more destructive of anthropocentrism than this one.”

In essence, heretofore obscure discoveries in biochemistry and genetics (largely studied at that time in simple bacteria) had upended two millennia of philosophy and religion that put humans at the center or apex of creation. “Man was the product of an incalculable number of fortuitous events,” Monod wrote. “The result of a huge Monte Carlo game, where our number eventually did come out, when it might not well have appeared.”

Le Hasard et la nécessité (Chance and Necessity) appeared in France in October 1970. It was a fairly technical book with several chapters on philosophy and genetics, and those appendices full of chemical diagrams. A first-time author, Monod did not know what reactions to expect.

The merde hit the fan.

The book received dozens of reviews across France and quickly became a bestseller—second only to the French translation of Erich Segal’s Love Story (this was France after all. After it was translated into English, reviews and interviews with Monod were featured in several of the most prominent British and American newspapers and magazines.

Many commentators immediately recognized the threat chance posed to traditional ideas of humanity’s origins and purpose. To Arthur Peacocke, a British biochemist turned prominent theologian, Monod had put forth “one of the strongest and most influential attacks of the century on theism.” A flurry of articles and books appeared with titles such as Anti-Chance: A Reply to Monod’s Chance and Necessity, Beyond Chance and Necessity, and God, Chance, and Necessity. Monod was invited to debate philosophers and theologians both in France and abroad, on television, radio, and in print.

American Calvinist theologian and pastor R.C. Sproul summed up the high stakes posed by chance in the first page of his book Not A Chance:

“It is not necessary for chance to rule in order to supplant God. Indeed, chance requires little authority at all if it is to depose God; all it needs to do the job is to exist. The mere existence of chance is enough to rip God from his cosmic throne. Chance does not need to rule; it does not need to be sovereign. If it exists as a mere impotent, humble servant, it leaves God not only out of date, but out of a job.” More than two hundred pages later, Sproul concluded:

“Chance as a real force is a myth. It has no basis in reality and no place in scientific inquiry. For science and philosophy to continue to advance in knowledge, chance must be demythologized once and for all.”

Sproul and other critics argued that what scientists perceived as chance merely reflected a lack of knowledge of true causes. Perhaps that was the expression of hope to which Monod alluded—the hope that as scientists learned more, our position on the role of chance would somehow be revised.

A SECOND CHANCE

The ensuing fifty years have not played out as either Monod or his detractors hoped. The Frenchman thought that the new insights from molecular biology should be a turning point for modern society-away from traditional beliefs about causes in the natural world toward one that embraced randomness and our chance existence.

Ha! Fat chance. The excitement and fuss stirred by Chance and Necessity simmered down, and Monod passed away a few years later. Surveys reveal that the majority of Americans, for example, continue to believe that everything on earth happens for His reasons.

But Monod’s critics should take no comfort. The province of chance in the biosphere and human life has been revised, although not at all in the scope or direction that they hoped.

The domain of chance has expanded into realms neither Monod nor anyone else imagined.

As we have learned much more about the history and workings of the planet, we have been startled to discover how the course of life has been buffeted by a variety of cosmological and geological accidents—without which we would not be here. As we have explored human history, we have seen how pandemics, droughts, and other civilization-changing episodes have been triggered by random, singular events in nature that easily might not have happened. And as we have probed human biology and the factors that impact our individual lives, we have caught chance red-handed, reigning over the often-thin line between life and death.

This book tells the stories that Monod could not—of astonishing discoveries from the planetary to the molecular scale, from great upheavals across the globe to the machinery of chance that operates within every cell of every creature, including ourselves. And while these discoveries vaporize the comforts of anthropocentrism, the story of chance, I hope you will come to agree, is much more than highfalutin philosophy or the refutation of theologians’ wishful thinking.

I hope that you are awed—awed by the power and the drama of asteroids slamming into the planet, of continents colliding, and of the rapid rising and falling of ice and oceans; awed by the realization that we live on (and are at the mercy of a planet that is far more unstable than our short lives perceive; awed by the knowledge of how random chance is at the source of all of the beautiful and wondrous creatures with whom we share the planet; awed by the unique invisible accidents that made each one of us; and awed by the fact that we humans, recent descendants of bands of hunter-gatherers who persevered through a period of exceptional chaos, have in just the last fifty years or so, figured all of this out!

My goal here is to be comprehensible without being comprehensive. It is almost trivial to claim that the world is the way it is or that we are here because of a long chain of chance, albeit fortunate, events. The explanatory power I seek comes from specificity. It is essential to unpack some of those events to appreciate how they shape the direction of life. The layout of the book follows a simple three-part logic. I’ll begin with inanimate, external chance events that have shaped the conditions for life (Part One, “Stuff Happens”), and then turn to the internal random mechanism within every creature that generates the adaptations to those conditions (Part Two, “A World of Mistakes”). Then, I bring the story to the personal level (Part Three, “23 and You”) and how chance impacts our natural lives, as well as our deaths. Our chance-driven existence shatters long-held beliefs about humanity’s place and raises challenging questions about the meaning and purpose of our lives. In the Afterword, I’ll offer some possible replies with the help of some special guests.

This is a relatively small book for a really big idea. Science has given us a handful of really big ideas over the centuries, but they have been received in funny ways. Darwin had a huge idea that was very simple to understand, and even though the evidence is massive and everywhere, many refuse to believe it. Einstein had a brand new idea, and even though few understand it or the evidence for it, most everyone seems to believe it. Monod had a great idea, but these days most people (other than scholars) have not heard of it, or of him.

My greatest hope, then, is that this short book might be chance’s second chance.

Sean B. Carroll, A Series of Fortunate Events: Chance and the Making of the Planet, Life, and You, Princeton University Press, 2020, pp. 6-12.

Modern biology as described by Monod pushes the linkage of probability, randomness and chance to the center. At the time, this was a very radical and profound way of looking at biology. If we combine Monod’s biology with theoretical physics like Lawrence KraussA Universe from Nothing: Why There Is Something Rather than Nothing, we realize that accidentality is the bedrock on which our knowledge of the universe is built.

Education and the “Knowability” Problem

There was a wonderful PBS Nature episode in 2006 called “The Queen of Trees” [full video, YouTube] which went into details about the survival strategy and rhythms and interactions with the environment of one tree in Africa and all the complexities this involves:

This Nature episode explores the evolution of a fig tree in Africa and its only pollinator, the fig wasp. This film takes us through a journey of intertwining relationships. It shows how the fig (queen) tree is life sustaining for an entire range of species, from plants, to insects, to other animals and even mammals. These other species are in turn life-sustaining to the fig tree itself. It could not survive without the interaction of all these different creatures and the various functions they perform. This is one of the single greatest documented (on video) examples of the wonders of our natural world; the intricacies involved for survival and ensuring the perpetual existence of species.

It shows us how fragile the balance is between survival and extinction.

One can begin to see that the tree/animal/bacteria/season/roots/climate interaction is highly complex and not quite fully understood to this day.

The fact that one tree yields new information every time we probe into it gives you a “meta” (i.e., meta-intelligent) clue that final theories of the cosmos and fully unified theories of physics will be elusive at best and unreachable at worst. If one can hardly pin down the workings of a single tree, does it sound plausible that “everything that is” from the electron to galaxy clusters to multiverses will be captured by an equation? The objective answer has to be: not particularly.

Think of the quest of the great unifiers like the great philosopherphysicist Hermann Weyl (died in 1955, like Einstein):

Since the 19th century, some physicists, notably Albert Einstein, have attempted to develop a single theoretical framework that can account for all the fundamental forces of nature–a unified field theory. Classical unified field theories are attempts to create a unified field theory based on classical physics. In particular, unification of gravitation and electromagnetism was actively pursued by several physicists and mathematicians in the years between the two World Wars. This work spurred the purely mathematical development of differential geometry.

Hermann Klaus Hugo Weyl (9 November, 1885 – 8 December, 1955) was a German mathematician, theoretical physicist and philosopher. Although much of his working life was spent in Zürich, Switzerland and then Princeton, New Jersey, he is associated with the University of Göttingen tradition of mathematics, represented by David Hilbert and Hermann Minkowski.

His research has had major significance for theoretical physics as well as purely mathematical disciplines including number theory. He was one of the most influential mathematicians of the twentieth century, and an important member of the Institute for Advanced Study during its early years.

Weyl published technical and some general works on space, time, matter, philosophy, logic, symmetry and the history of mathematics. He was one of the first to conceive of combining general relativity with the laws of electromagnetism. While no mathematician of his generation aspired to the “universalism” of Henri Poincaré or Hilbert, Weyl came as close as anyone.

Weyl is quoted as saying:

“I am bold enough to believe that the whole of physical phenomena may be derived from one single universal world-law of the greatest mathematical simplicity.”

(The Trouble with Physics, Lee Smolin, Houghton Mifflin Co., 2006, page 46)

This reminds one of Stephen Hawking’s credo that he repeated often and without wavering, that the rational human mind would soon understand “the mind of God.”

This WeylHawkingEinstein program of “knowing the mind of God” via a world-equation seems both extremely charming and beautiful, as a human quest, but potentially mono-maniacal à la Captain Ahab in Moby-Dick. The reason that only Ishmael survives the sinking of the ship, the Pequod, is that he has become non-monomaniacal and accepts the variegatedness of the world and thus achieves a more moderate view of human existence and its limits. “The Whiteness of the Whale” chapter in the novel gives you Melville’s sense (from 1851) of the unknowability of some final world-reality or world-theory or world-equation.

Pathogens-Watching

New Articles in PLOS Pathogens

Insertive Condom-Protected and Condomless Vaginal Sex Both Have a Profound Impact on the Penile Immune Correlates of HIV Susceptibility

by Avid Mohammadi, Sareh Bagherichimeh, Yoojin Choi, Azadeh Fazel, Elizabeth Tevlin, Sanja Huibner, Zhongtian Shao, David Zuanazzi, Jessica L. Prodger, Sara V. Good, Wangari Tharao & Rupert Kaul

Summary: In heterosexual men, the penis is the primary site of Human Immunodeficiency Virus (HIV) acquisition. Levels of inflammatory cytokines in the coronal sulcus are associated with an increased HIV risk, and we hypothesized that these may be altered after insertive penile sex. Therefore, we designed the Sex, Couples and Science Study (SECS study) to define the impact of penilevaginal sex on the penile immune correlates of HIV susceptibility. We found that multiple coronal sulcus cytokines increased dramatically and rapidly after sex, regardless of condom use, with a return to baseline levels by 72 hours. The changes observed after condomless sex were strongly predicted by cytokine concentrations in the vaginal secretions of the female partner, and were similar in circumcised and uncircumcised men. We believe that these findings have important implications for understanding the immunopathogenesis of penile HIV acquisition; in addition, they have important implications for the design of clinical studies of penile HIV acquisition and prevention.

[Archived PDF]

Engineering, Decoding and Systems-Level Characterization of Chimpanzee Cytomegalovirus

by Quang Vinh Phan, Boris Bogdanow, Emanuel Wyler, Markus Landthaler, Fan Liu, Christian Hagemeier & Lüder Wiebusch

Summary: Human cytomegalovirus (HCMV) infection is associated with systemic disease in immunocompromised individuals and congenitally infected neonates. Animal CMVs and their bacterial artificial chromosome (BAC) clones have been utilized as models for CMV infection and thereby contributed immensely to the understanding of pathogenesis, host immune response and underlying molecular mechanism of CMV infections. As the closest relative to HCMV, the chimpanzee CMV (CCMV) holds a great potential as a model system for HCMV infection but its application was limited due to the lack of tools and data for functional genomic analyses. Here, the cloning of the CCMV as a BAC vector made its viral genome available to gene targeting techniques that allow the efficient application of reverse genetic strategies. Furthermore, the multi-omic datasets created in this study provide an in-depth view of the viral gene repertoire and the host cell responses to infection, confirming the close phylogenetic relationship between HCMV and CCMV on a system level. Taken together, the newly established CCMVBAC system presents a framework for HCMV modeling and comparative studies to address key questions in evolutionary processes and infection mechanisms.

[Archived PDF]

RplI Interacts with 5′ UTR of exsA to Repress Its Translation and Type III Secretion System in Pseudomonas aeruginosa

by Dan Wang, Xinxin Zhang, Liwen Yin, Qi Liu, Zhaoli Yu, Congjuan Xu, Zhenzhen Ma, Yushan Xia, Jing Shi, Yuehua Gong, Fang Bai, Zhihui Cheng, Weihui Wu, Jinzhong Lin & Yongxin Jin

Summary: Ribosomes provide all living organisms the capacity to synthesize proteins. The production of many ribosomal proteins is often controlled by an autoregulatory feedback mechanism. Paeruginosa is an opportunistic human pathogen and its type III secretion system (T3SS) is a critical virulence determinant in host infections. In this study, by screening a Tn5 mutant library, we identified rplI, encoding ribosomal large subunit protein L9, as a novel repressor for the T3SS. Further exploring the regulatory mechanism, we found that the RplI protein interacts with the 5’ UTR (5’ untranslated region) of exsA, a gene coding for transcriptional activator of the T3SS. Such an interaction likely blocks ribosome loading on the exsA 5’ UTR, inhibiting the initiation of exsA translation. The significance of this work is in the identification of a novel repressor for the T3SS and elucidation of its molecular mechanism. Furthermore, this work provides evidence for individual ribosomal protein regulating mRNA translation beyond its autogenous feedback control.

[Archived PDF]

Structure of a Bacterial Rhs Effector Exported by the Type VI Secretion System

by Patrick Günther, Dennis Quentin, Shehryar Ahmad, Kartik Sachar, Christos Gatsogiannis, John C. Whitney & Stefan Raunser

Summary: Bacteria have developed a variety of strategies to compete for nutrients and limited resources. One system widely used by Gram-negative bacteria is the T6 secretion system which delivers a plethora of effectors into competing bacterial cells. Known functions of effectors are degradation of the cell wall, the depletion of essential metabolites such as NAD+ or the cleavage of DNA. RhsA is an effector from the widespread plant-protecting bacteria Pseudomonas protegens. We found that RhsA forms a closed cocoon similar to that found in bacterial Tc toxins and metazoan teneurin proteins. The effector cleaves its polypeptide chain by itself in three pieces, namely the N-terminal domain including a seal, the cocoon and the actual toxic component which potentially cleaves DNA. The toxic component is encapsulated in the large cocoon, so that the effector producing bacterium is protected from the toxin. In order for the toxin to exit the cocoon, we propose that the seal, which closes the cocoon at one end, is removed by mechanical forces during injection of the effector by the T6 secretion system. We further hypothesize about different scenarios for the delivery of the toxin into the cytoplasm of the host cell. Together, our findings expand the knowledge of the mechanism of action of the T6 secretion system and its essential role in interbacterial competition.

[Archived PDF]

Non-Neutralizing Antibodies Targeting the Immunogenic Regions of HIV-1 Envelope Reduce Mucosal Infection and Virus Burden in Humanized Mice

by Catarina E. Hioe, Guangming Li, Xiaomei Liu, Ourania Tsahouridis, Xiuting He, Masaya Funaki, Jéromine Klingler, Alex F. Tang, Roya Feyznezhad, Daniel W. Heindel, Xiao-Hong Wang, David A. Spencer, Guangnan Hu, Namita Satija, Jérémie Prévost, Andrés Finzi, Ann J. Hessell, Shixia Wang, Shan Lu, Benjamin K. Chen, Susan Zolla-Pazner, Chitra Upadhyay, Raymond Alvarez & Lishan Su

Summary: In the past decade, HIV-1 has infected an estimated 1.5 to 2 million people every year, but vaccines needed to control this pandemic are unavailable. Among vaccines tested in the human efficacy trials, the RV144 vaccine regimen showed a modest efficacy and revealed non-neutralizing antibodies against the virus envelope glycoproteins as a correlate of reduced virus acquisition. To design more efficacious HIV-1 vaccines, a better understanding about antiviral mechanisms of these antibodies is needed. Here non-neutralizing monoclonal antibodies against two immunogenic sites on the virus envelope were evaluated for passive administration to humanized mice that were subsequently challenged with HIV-1. The antibodies did not block mucosal HIV-1 infection but reduced virus burden. The level of virus reduction correlated with the antibody binding potency and the effector functions mediated through their Fc fragments, which included antibody-dependent phagocytosis and complement activation, but not the commonly studied antibody-dependent cellular cytotoxicity. The importance of the Fc functions was further demonstrated by reduced virus control when mutations were introduced to decrease Fc activities. This study provides new evidence for the important contribution of multiple Fc-dependent antibody functions in immune control against HIV-1.

[Archived PDF]

Variability in an Effector Gene Promoter of a Necrotrophic Fungal Pathogen Dictates Epistasis and Effector-Triggered Susceptibility in Wheat

by Evan John, Silke Jacques, Huyen T. T. Phan, Lifang Liu, Danilo Pereira, Daniel Croll, Karam B. Singh, Richard P. Oliver & Kar-Chun Tan

Summary: Breeding for durable resistance to fungal diseases in crops is a continual challenge for crop breeders. Fungal pathogens evolve ways to overcome host resistance by masking themselves through effector evolution and evasion of broad-spectrum defense responses. Association studies on mapping populations infected by isolate mixtures are often used by researchers to seek out novel sources of genetic resistance. Disease resistance quantitative trait loci (QTL) are often minor or inconsistent across environments. This is a particular problem with septoria diseases of cereals such as septoria nodorum blotch (SNB) of wheat caused by Parastagonospora nodorum. The fungus uses a suite of necrotrophic effectors (NEs) to cause SNB. We characterized a genetic element, called PE401, in the promoter of the major NE gene Tox1, which is present in some Pnodorum isolates. PE401 functions as a transcriptional repressor of Tox1 and exerts epistatic control on another major SNB resistance QTL in the host. In the context of crop protection, constant surveillance of the pathogen population for the frequency of PE401 in conjunction with NE diversity will enable agronomists to provide the best advice to growers on which wheat varieties can be tailored to provide optimal SNB resistance to regional pathogen population genotypes.

[Archived PDF]

Mutational Analysis of Aedes aegypti Dicer 2 Provides Insights into the Biogenesis of Antiviral Exogenous Small Interfering RNAs

by Rommel J. Gestuveo, Rhys Parry, Laura B. Dickson, Sebastian Lequime, Vattipally B. Sreenu, Matthew J. Arnold, Alexander A. Khromykh, Esther Schnettler, Louis Lambrechts, Margus Varjak & Alain Kohl

Summary: Aedes aegypti mosquitoes that transmit human-pathogenic viruses rely on the exogenous small interfering RNA (exo-siRNA) pathway as part of antiviral responses. This pathway is triggered by virus-derived double-stranded RNA (dsRNA) produced during viral replication that is then cleaved by Dicer 2 (Dcr2) into virus-derived small interfering RNAs (vsiRNAs). These vsiRNAs target viral RNA, leading to suppression of viral replication. The importance of Dcr2 in this pathway has been intensely studied in the Drosophila melanogaster model but is largely lacking in mosquitoes. Here, we have identified conserved and functionally relevant amino acids in the helicase and RNase III domains of Aeaegypti Dcr2 that are important in its silencing activity and antiviral responses against Semliki Forest virus (SFV). Small RNA sequencing of SFV-infected mosquito cells with functional or mutated Dcr2 gave new insights into the nature and origin of vsiRNAs. The findings of this study, together with the different molecular tools we have previously developed to investigate the exo-siRNA pathway of mosquito cells, have started to uncover important properties of Dcr2 that could be valuable in understanding mosquito-arbovirus interactions and potentially in developing or assisting vector control strategies.

[Archived PDF]

Probing the Structure and Function of the Protease Domain of Botulinum Neurotoxins Using Single-Domain Antibodies

by Kwok-ho Lam, Jacqueline M. Tremblay, Kay Perry, Konstantin Ichtchenko, Charles B. Shoemaker & Rongsheng Jin

Summary: Botulinum neurotoxins (BoNTs) are extremely toxic to humans by causing flaccid paralysis of botulism. The catalytic light chain (LC) of BoNTs is the warhead of the toxin, which is mainly responsible for BoNT’s neurotoxic effects. As an endopeptidase, LC is delivered by the toxin to inside neurons where it specifically cleaves neuronal SNARE proteins and causes muscle paralysis. While the currently available equine and human antitoxin sera can prevent further intoxication, they do not promote recovery from paralysis that has already occurred. We strike to develop single-domain variable heavy-chain (VHH) antibodies targeting the LC of BoNT/A (LC/A) and BoNT/B (LC/B) as antidotes to inhibit or eliminate the intraneuronal LC protease. Here, we report the identification and characterization of large panels of new and unique VHHs that bind to LC/A or LC/B. Using a combination of X-ray crystallography and biochemical assays, we reveal that VHHs exploit diverse mechanisms to interact with LC/A and LC/B and inhibit their protease activity, and such knowledge can be harnessed to predict their specificity towards different toxin subtypes within each serotype. We anticipate that the new VHHs and their characterization reported here will contribute to the development of improved botulism therapeutics having high potencies and broad specificities.

[Archived PDF]

B Cell Overexpression of FCRL5 and PD-1 Is Associated with Low Antibody Titers in HCV Infection

by Clinton O. Ogega, Nicole E. Skinner, Andrew I. Flyak, Kaitlyn E. Clark, Nathan L. Board, Pamela J. Bjorkman, James E. Crowe Jr., Andrea L. Cox, Stuart C. Ray & Justin R. Bailey

Summary: Antiviral immunity relies on production of protective immunoglobulin G (IgG) by B cells, but many hepatitis C virus (HCV)-infected individuals have very low levels of HCV-specific IgG in their serum. Elucidating mechanisms underlying this suboptimal IgG expression remains paramount in guiding therapeutic and vaccine strategies. In this study, we developed a highly specific method to capture HCV-specific B cells and characterized their surface protein expression. Two proteins analyzed were Fc receptor-like protein 5 (FCRL5), a cell surface receptor for IgG, and programmed cell death protein-1 (PD-1), a marker of lymphocyte activation and exhaustion. We measured serum levels of anti-HCV IgG in these subjects and demonstrated that overexpression of FCRL5 and PD-1 on memory B cells was associated with reduced anti-E2 IgG levels. This study uses HCV as a viral model, but the findings may be applicable to many viral infections, and they offer new potential targets to enhance antiviral IgG production.

[Archived PDF]