Immunogenicity of bacteriophages (2023)


Bacteriophages (phages) are both the most abundant and least understood organisms on the planet. Like all other viruses, they must hijack the cellular machinery of a host cell to replicate. Thus, phages can be highly exploitative, exerting high control over the number and behavior of bacteria for their own existence [1]. This is the principle behind the practice of phage therapy, an antimicrobial approach that uses strictly virulent (see Glossary) phages to target and acutely kill harmful bacterial in the body [2., 3., 4.]. However, temperate phages establish conditional symbiotic relationships by sharing their genetic information (i.e., lysogenic conversion) to enhance the fitness and survival of both the infecting phage and host cell. Other phages have profound fitness effects on the host population and often remain sublethal by keeping enough hosts alive to continuously release new virions [5., 6., 7.]. On the whole, phages are important predators of bacteria; they shape the densities, function, structure, and evolution of natural microbial communities, and they are potential agents for biotechnological and therapeutic applications [2,5,8,9].

Less well understood are the double-edged sword relationships between phages and their human hosts. Humans are constantly eating and breathing phages from the environment [8]. Thus, humans may be considered both incidental and long-term hosts to diverse communities of phages that colonize the luminal and mucosal sites in the body [10]. Although it is well recognized that phages are incapable of directly causing human disease, phage predation of bacteria that colonize the body have potentially fatal consequences to their host [11]. For example, enterohemorrhagic Escherichia coli interacts with a Shiga toxin–encoding temperate phage, and together they cause severe gastroenteritis disease in humans [11]. Indeed, many phage–bacteria interactions influence the functions of tissues, organs, and systems of humans [12,13]. The abundance of phages and their ubiquity within the body [10,14] also appear to aid the body’s defenses. Phage lytic activity removes harmful bacteria at sites of infection [15] and enhances protective mucosal barriers [16]. At the same time, the immune system may be sensing the vast diversity of phages to evoke diverse immune responses. Phage sensing may influence the host immune response to invasive pathogens [17,18], enhance inflammatory immune responses [19,20], or provide tonic stimulation essential for host health, particularly by regulating immune homeostasis [21]). Because the immune system is constantly ‘on guard,’ there is the potential for deleterious responses to phages. Specific resident phage community compositions (viromes) have been correlated with multiple chronic immunological diseases, including inflammatory bowel disease, Parkinson’s disease, and obesity [22., 23., 24.].

Phage immunogenicity, as we understand it today, suggests that the human immune system actively reacts to some phages while simultaneously tolerating the vast majority of them. Here we review phage immunogenicity by focusing on the direct interactions between phages and human immune cells and findings that indicate how phages influence various immune functions (Table 1). We provide an overview of phage varieties, contact sites, viral sensors, and signaling pathways in cell subsets. Where there are gaps in our knowledge, we describe how the host reacts to eukaryotic viruses with similar properties to phages. Although techniques are improving to interrogate phage–human cell interactions, much work remains to reach consensus on phage immunogenicity in health and disease.

(Video) Do phage influence the immune response?

Section snippets

Phage virion types

Phages are an incredibly diverse group of viruses whose breadth is under constant expansion [25] (Figure 1). By far the most abundant type in the body are Caudoviricetes double-stranded (ds) DNA phages, whereas less abundant are Tectiliviricetes dsDNA phages, Faserviricetes and Malgrandaviricetes filamentous single-stranded (ss) DNA phages, Vidaverviricetes dsRNA phages, and Leviviricetes ssRNA phages [9]. Most phages protect their genome within a proteinaceous capsid that can be icosahedral

Host contact

A vast number of phages are living on and within the human body [10], which begin to accumulate at birth [13]. Phages, however, are not known to classically ‘infect’ human cells, but we now know they do invade them. Eukaryotic viruses use two main routes of entry into the cell: direct fusion with the plasma membrane or endocytosis. So far, phages appear to exploit the latter to invade human cells [17,20,30]. ‘Endocytosis’ is an umbrella term that describes active internalization of

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Immune sensing of phages

Much like our five senses help us understand what is happening around us, pattern recognition receptors (PRRs) are vital for immune cells to understand what is happening within us. The body’s innate immune system comprises numerous cells and molecules with specificity to differentiate between viral and host cell features. Toll-like receptors (TLRs) are transmembrane PRRs that are crucial in the initiation of innate and downstream adaptive immune responses [47]. Humans express 10 TLRs, and, of

Phage–phagocyte interaction

DCs are professional antigen-presenting cells (APCs) and the predominant antiviral immune cell [64]. DC subtypes express an abundance of nucleic acid sensors, including TLR3, TLR7, and TLR9, and eukaryotic virus-activated DCs tend to cause the release of type I IFNs and other proinflammatory cytokines [64] (Figure 2). Whether phages can activate DCs in a similar manner remains unclear. P. aeruginosa ssDNA filamentous phage Pf4 was found to inhibit lipopolysaccharide (LPS)-induced TNF production

Phage–epithelium interaction

Phages interact with the single continuous layer of columnar IECs that surround the lumen and serve as a barrier and absorptive surface. IECs express a broad range of PRRs and have many immune-regulatory functions, including in response to virus detection [72]. Given the constant presence of phages at mucosal epithelial barriers, these interactions likely have profound influences on host immune and gastrointestinal homeostasis; yet, they are poorly characterized. Although TLR9 is a dsDNA sensor

Phage-induced cytokine responses

Phages do not infect host cells, but some phages elicit immune responses, as we discuss here. However, what is currently not clear is whether phage-elicited responses are harmful or instead promote tissue homeostasis. In addition, the exact immunological mechanisms and responses are mixed in different tissues and cells. This may be in part due to context: Exposure to microbes in commensal settings, such as the gut microbiota, tends to evoke largely anti-inflammatory and regulatory responses [76

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Adaptive immunity to phages

Adaptive immune responses are shaped by the quality of the initial innate immune responses. There are two main effector mechanisms of adaptive immunity: humoral mediated by B cells and cellular mediated primarily by T cells. When a B cell recognizes an extracellular antigen such as a viral capsid, it proliferates and differentiates into specialized plasma cells that secrete antibodies. These antibodies can bind to the activating stimulus, either interfering with its function, inducing

Concluding remarks and future perspectives

For more than 200 million years, both phages and bacteria have dominated the human body and the food we eat and thus have shaped our evolution [103]. The human innate immune system is astonishingly multifaceted, consisting of a wide array of cells, signaling chains, and effector molecules dedicated to the elimination of microbial intruders. Despite environments teeming with phages and the use of phages as therapeutic agents, little is understood about how phages interact with mammalian cells.


We gratefully acknowledge funding from the San Diego State University Graduate Fellowship and Rees-Stealy Research Foundation (T.L.) and Cystic Fibrosis Foundation Postdoctoral Research Fellowship Award (K.C.-J.). We also thank Ryan Cook (University of Nottingham) and Andrew Sue (San Diego State University) for helpful discussions.

Declaration of interests

No interests are declared.

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Adaptive immune cells
white blood cells (lymphocytes) that respond to specific and unique antigens; differ from innate immunity, which recognizes broadly conserved molecular patterns.

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a molecular structure that can be recognized by an adaptive immune cell receptor.

Antigen-presenting cells (APCs)
innate immune cells that capture antigens and present them to lymphocytes to enable antigen-specific immune responses.

a mixture of phages from two or more phage strains given as a single

© 2023 Elsevier Ltd. All rights reserved.


Are bacteriophages immunogenic? ›

Therapeutic phages are being employed for vaccination and treatment of cancer and bacterial infections. Their natural immunogenicity triggers intertwined interactions with innate and adaptive immune cells that might influence therapy.

What is the immune response against phages? ›

The innate immunity has a negative effect on the phage survival and leads to its removal. Subsequently the bacteria are no longer infected by the phage, and a rise in bacteria is observed. (C) Phage susceptibility to the innate immune response, considering the anti-inflammatory property of the phage.

Does the immune system target bacteriophages? ›

The cells of the innate immune system share the ability to sense microbe-specific material, such as bacterial endotoxin and that of bacteriophage, through a family of receptors called pathogen recognition receptors (PRR) that recognize pathogen-associated molecular patterns (PAMPs).

Are humans immune to phages? ›

Antiphage adaptive immunity is likewise suspected to adversely affect the outcome of intravenous phage therapy. Although research on antiphage antibodies in humans is limited, one study suggests that many individuals have preexisting, neutralizing antibodies against phages commonly used in phage therapy (134).

Which of the following is the most immunogenic? ›

The K antigen is the most immunogenic antigen after the antigens of the ABO and Rh blood group systems.

How do bacteria get immunity against bacteriophage attacks? ›

Bacteria can evade the phage attack via several mechanisms and some of these strategies include the following: DNA restriction-modification (R-M), spontaneous mutations, blocking of phage receptors, production of competitive inhibitors, and extracellular matrix and acquired immunity via the clustered regularly ...

Why can't phages infect humans? ›

Bacteriophages are viruses infecting bacterial cells. Since there is a lack of specific receptors for bacteriophages on eukaryotic cells, these viruses were for a long time considered to be neutral to animals and humans.

How does bacteriophage differ from viruses that affect us? ›

Virus: ↑ A type of microbe that can infects cells. Human viruses infect human cells, plant viruses infect plant cells, etc. Bacteriophage: ↑ A virus that infects bacteria, also called a phage. DNA: ↑ The molecule that carries all the information in the form of genes needed to produce proteins.

Do phages may trigger the immune system to overreact or cause an imbalance? ›

Phages may trigger the immune system to overreact or cause an imbalance. Some types of phages don't work as well as other kinds to treat bacterial infections. There may not be enough kinds of phages to treat all bacterial infections. Some phages may cause bacteria to become resistant.

Why don't we use phages instead of antibiotics? ›

Second, phage takes a longer time to employ in a treatment compared to antibiotics. Because a single type of phage can only infect a few species of bacteria, phage selection has to be done with care.

Can phages cross the blood brain barrier? ›

Filamentous bacteriophage can enter the brain across the BBB.

Are phages allowed in the US? ›

Yet, phage therapy has largely existed on the fringes of medicine, particularly in Western countries like the U.S., where it is occasionally approved for compassionate use (i.e., used on an emergency basis when no other approved therapies are available).

Do bacteriophages infect other viruses? ›

Like all viruses, bacteriophages are very species-specific with regard to their hosts and usually only infect a single bacterial species or even specific strains within a species.

Are bacteriophages DNA or RNA viruses? ›

Bacteriophage have either DNA or RNA as their genetic material, in either circular or linear configuration, as a single- or a double-stranded molecule.

How effective are bacteriophages? ›

They are the most common biological entities in nature, and have been shown to effectively fight and destroy multi-drug resistant bacteria. Namely, when all antibiotics fail, phages still succeed in killing the bacteria and may save a life from an infection.

What is the difference between immunity and immunogenicity? ›

So what is the difference between immunity and immunogenicity. Very briefly, immunity is what we want. We need a good defense immune system or immune response on the other hand immunogenicity of biologics is usually undesirable. but immunogenicity is derived from immunity.

Why is immunogenicity so important? ›

Immunogenicity assays provide a way to measure the potential immune responses of biologics and biosimilars. Often a single biologic will require a panel of assays to produce a thorough picture of potential immunogenicity.

What is the second most immunogenic antigen? ›

Other than antigens in the ABO system, Rh (D) is the most immunogenic red cell antigen, followed by K in the Kell blood group system. Other immunogenic antigens include c and E in the Rh system.

Do bacteriophages cause drug resistance? ›

Bacteriophage (“phage”) are viruses that can infect and kill bacteria, but also natural drivers of antimicrobial resistance (AMR) evolution by transduction, when they carry non-phage DNA between bacteria, including AMR genes.

Can bacteria resist bacteriophages? ›

Bacteria can develop resistance to phages, as they do to antibiotics.

Do bacteriophages target good bacteria? ›

Phages useful for 'precision editing' within body

“Antibiotics kill bacteria, but they do not discriminate between good and harmful bacteria,” he said. “Phages are so specific for bacterial strains that even within one species of bacteria, the phage might not be able to recognize all strains.”

Are phages the deadliest thing in the world? ›

From all these, we can conclude that the most abundant killer on the earth- bacteriophage could be given the tag of deadliest being as it devours mercilessly numerous bacteria every second.

Are bacteriophages harmful to humans if they? ›

When the phage infects a new bacterium, it introduces the original host bacterium's DNA into the new bacterium. In this way, phages can introduce a gene that is harmful to humans (e.g., an antibiotic resistance gene or a toxin) from one bacterium to another.

Why are bacteriophages better than antibiotics? ›

Phages won't harm any of your cells except for the bacterial cells that they're meant to kill. Phage therapy has fewer side effects than antibiotics. On the other hand, most antibiotics have a much wider host range. Some antibiotics can kill a wide range of bacterial species at the same time.

What are the 3 types of bacteriophages? ›

There are three basic structural forms of phage: an icosahedral (20-sided) head with a tail, an icosahedral head without a tail, and a filamentous form.

What diseases are caused by bacteriophage? ›

These include diphtheria, botulism, Staphylococcus aureus infections (i.e. skin and pulmonary infections, food poisoning, and toxic shock syndrome), Streptococcus infections, Pasteurella infections, and cholera, Shiga toxin-producing Shigella and Escherichia coli infections, and Pseudomonas aeruginosa infections.

Why do bacteriophages only infect certain bacteria? ›

They have to match or the virus can not enter the host cell and can not infect it. Bacteriophages (or 'phages) only can infect bacteria for this reason.

What is a limitation of phages? ›

The great specificity of phages is a disadvantage when the exact species of infecting bacteria is unknown or if there is a multiple infection. For good results, the efficacy of phages against the infecting bacteria should be tested prior to application in the lab.

Can phages make you sick? ›

Phages aren't like other viruses that make you sick. They can only infect bacteria.

Can a bacteria be infected by multiple phages? ›

From a population perspective, high MOI exposure could cause faster phage growth and bacterial lysis since more cells will be infected by at least one phage. However, within the population, there will also be cases of bacterial cells being infected by more than one phage.

How do phages affect humans? ›

In the indirect interaction with the host microorganism, phages can affect the human host through induction of increased intestinal permeability by reduced Lactobacillus spp. and Faecalibacterium spp., which are important regulators of the intestinal barrier and create the possibility for phage circulation in the CSF.

What happens when a phage attacks a bacterial cell? ›

The phage infection cycle seems to be simple but extremely efficient: a single phage injects its genome into a bacterial cell, switching the cells' programme in its favour so the host cell will eventually die and release about 100 new phage particles.

Why are phages not used in UK? ›

In the UK, however, there are no specific regulations on the clinical use of phages, so they fall under the regulatory framework of unlicenced medicines and the Medicines and Healthcare products Regulatory Agency requires their production within the UK to follow Good Manufacturing Practice (GMP), both for compassionate ...

Can phages be used as vaccines? ›

Phage Display Vaccines

Both filamentous and tailed phages have since been used to generate immunity against a variety of viral [26–28], parasitic [29], and cancer [30] antigens. These approaches have been used extensively in a broad range of in vivo pre-clinical models.

What does Russia use instead of antibiotics? ›

Phage therapy is used in Russia, Georgia and Poland, and was used prophylactically for a time in the Soviet army. In Russia, extensive research and development soon began in this field. In the United States during the 1940s, commercialization of phage therapy was undertaken by Eli Lilly and Company.

Do bacteriophages have antigens? ›

Phages therefore present antigens to immune cells in a highly ordered and repetitive manner. This review discusses the use of phage with adjuvanting activity as antigen delivery vehicles for vaccination against infectious disease and cancer.

What is immunogenic bacteria? ›

The immunogenicity of bacteria is pivotal for the strength of provoking an immune response. As demonstrated in recently published studies, the immunogenicity is dependent on the structure of different MAMPs (e.g., LPS) and consequently to the binding affinity to PRRs (59).

What category are bacteriophages in? ›

Characteristics of bacteriophages

Phages are classified in a number of virus families; some examples include Inoviridae, Microviridae, Rudiviridae, and Tectiviridae. Like all viruses, phages are simple organisms that consist of a core of genetic material (nucleic acid) surrounded by a protein capsid.

Which type of virus are bacteriophages classified as? ›

A bacteriophage (/bækˈtɪərioʊfeɪdʒ/), also known informally as a phage (/ˈfeɪdʒ/), is a duplodnaviria virus that infects and replicates within bacteria and archaea. The term was derived from "bacteria" and the Greek φαγεῖν (phagein), meaning "to devour".

Do bacteriophages usually have ssRNA? ›

Bacteriophages belonging to the family Leviviridae are among the simplest known viruses, exhibiting positive-sense single-stranded RNA (ssRNA) genomes of just 3.5-4.5 kilobases, typically encoding only 4 proteins. Morphologically, Leviviridae particles present a spherical or isometric shape with a diameter of 30 nm.

Can bacteriophage be used as a vaccine? ›

Nowadays, two main types of phage-based vaccines have been widely recognized: (1) phage display vaccines and (2) bacteriophage DNA vaccines [6,10]. The combination of these two strategies has resulted in the development of a third strategy, (3) the hybrid phage vaccine.

Which antigen is most immunogenic? ›

The D antigen is the most immunogenic, meaning it provokes an immune response that makes it most likely to cause a transfusion reaction in the recipient.

What is the difference between immunogenicity and antigen? ›

The term immunogenicity refers to the ability of a substance to induce cellular and humoral immune response, while antigenicity is the ability to be specifically recognized by the antibodies generated as a result of the immune response to the given substance.

What causes immunogenicity? ›

Posttranslational modifications can have direct or indirect effects on immunogenicity. The modified part of the biotherapeutic itself could induce an immune response, or its presence can affect the tertiary structure of the protein subtly causing the biotherapeutic to become immunogenic [4].

Are bacteriophages harmful to humans? ›

In these cases, bacteria become very dangerous. Bacteriophages are viruses that infect bacteria but are harmless to humans. To reproduce, they get into a bacterium, where they multiply, and finally they break the bacterial cell open to release the new viruses. Therefore, bacteriophages kill bacteria.

Is bacteriophage virus DNA or RNA? ›

RNA is the genetic material of the bacteriophage but RNA is not the sole genetic material of the bacteriophage while DNA is also a genetic material of the bacteriophage. mRNA is also known as messenger RNA which is responsible for the translation of proteins.

Why can't bacteriophages infect human cells? ›

Bacteriophages are viruses infecting bacterial cells. Since there is a lack of specific receptors for bacteriophages on eukaryotic cells, these viruses were for a long time considered to be neutral to animals and humans.

What are the 2 types of bacteriophage? ›

There are two primary types of bacteriophages: lytic bacteriophages and temperate bacteriophages. Bacteriophages that replicate through the lytic life cycle are called lytic bacteriophages, and are so named because they lyse the host bacterium as a normal part of their life cycle.

Are bacteriophages considered viruses? ›

Phages, formally known as bacteriophages, are viruses that solely kill and selectively target bacteria. They are the most common biological entities in nature, and have been shown to effectively fight and destroy multi-drug resistant bacteria.


1. Disrupting life science: How VHH antibodies will shape future research
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2. Developability: Evaluating Specificity, Immunogenicity, Functionality, and Manufacturability...
(BioProcess International)
3. Phages as Therapeutic Tools Against Multidrug Resistant Bacteria
(American Society for Microbiology)
4. Guy Hermans: Using synthetic antibody libraries to overcome poor immunogenicity
(ProImmune thinkpeptides)
5. Jeremy Fry: An integrated approach to managing immunogenicity risk and drug immune modulation
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6. Jeremy Fry: Tools and technologies for comprehensive immunogenicity risk management
(ProImmune thinkpeptides)
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