{"id":8549,"date":"2019-11-15T16:27:18","date_gmt":"2019-11-15T15:27:18","guid":{"rendered":"https:\/\/www.phage.help\/unkategorisiert\/phage-specific-diverse-effects-of-bacterial-viruses-on-the-immune-system-2\/"},"modified":"2019-11-15T16:27:18","modified_gmt":"2019-11-15T15:27:18","slug":"phage-specific-diverse-effects-of-bacterial-viruses-on-the-immune-system-2","status":"publish","type":"post","link":"https:\/\/www.phage.help\/en\/bacteriophages\/phage-specific-diverse-effects-of-bacterial-viruses-on-the-immune-system-2\/","title":{"rendered":"Phage-specific diverse effects of bacterial viruses on the immune system"},"content":{"rendered":"

“With the increasing threat of antibiotic resistance, interest in phage therapy (PT) as a potential solution to this crisis has rapidly grown. Recently, several reports have been published describing successful treatment of patients with life-threatening antibiotic-resistant bacterial infections, including lung transplant recipients and treatment with genetically modified phages. Furthermore, the first PT center was opened in the US, following the establishment of a similar unit in Belgium. These developments confirm our decision to establish the first such unit in 2005, operating in accordance with UKORE and national regulations, which has helped pave the way for future advancements in PT as an option to combat the antibiotic resistance crisis. Extensive evidence from observational studies indicates the safety of PT. Moreover, several clinical trials have been completed (including one according to all required standards of good medical practice and evidence-based medicine) and more are ongoing. However, these studies have yet to provide definitive proof of PT’s efficacy [1-4]. While the struggle for the registration and market introduction of phages as a medicine continues, parallel data has accumulated suggesting that phages can interact not only with bacteria but also with eukaryotic cells (including immune system cells). Therefore, it cannot be ruled out that future research, following the discovery of phages, will shift towards phage-immune system interactions, whereas until now, work on phage interactions with their natural target (bacteria) has dominated. It remains to be hoped that simultaneous progress in both research areas can yield positive results for human health, both in combating antibiotic-resistant bacterial infections and in developing new anti-inflammatory and immunomodulatory substances with minimal toxicity and satisfactory efficacy [4,5]. <\/em><\/p>\n

We have formulated a hypothesis stating that phages present in the gut can migrate to blood, lymph, and organs, mediate anti-inflammatory effects, and contribute to immunological tolerance and immune homeostasis \u2013 both in situ and in other parts of the body [6]. Study results confirm this, and moreover, over 30 billion phages undergo transcytosis from the intestinal epithelium daily, spreading to blood, lymph, and organs [7]. Additionally, other cell types, including immune cells, can also take up phages via the endocytic pathway [8]. <\/em><\/p>\n

The newly emerging concept of the phage, encompassing not only bacterial predators but also potential anti-inflammatory and immunomodulatory substances, requires detailed further investigation. A critical point that needs clarification is phage specificity in mediating certain immune responses. Phages are known for their high specificity towards bacteria, which has been established for decades and is used in phage typing for the classification of different bacterial strains. Are immunotropic activities also phage-specific, or do phages induce similar responses regardless of the phage type? <\/em><\/p>\n

It is assumed that phage capsid proteins may be primarily responsible for the biological properties of the phage not related to interactions with bacteria. These proteins differ in their immunogenicity and can elicit various antibody responses to phages, which also depends on the route of administration. Furthermore, different strains of a homologous phage, recognizing a particular bacterium, can express different proteins [9,10] and confer different functions to the phage (e.g., persistence in circulation and anti-metastatic effects). For example, a T4 phage mutant, HAP1, with a non-functional Hoc protein, is more susceptible to the Kupffer cells of the liver and is cleared faster than its parent strain. There are also differences between HAP1 and T4 phages in their interactions with T-cells and fibrinogen [11,12]. <\/em>
\nInitial studies on the effects of phages on other immune functions suggest that the effects may also differ depending on the phage type. For example, purified T4 coliphage inhibits CD3-TCR complex-induced human T-cell proliferation, while purified staphylococcal phage exerts a co-stimulatory effect [12]. A detailed study on staphylococcal and Pseudomonas phages showed that, although these phages induced similar responses in human peripheral blood mononuclear cells by upregulating the gene expression of anti-inflammatory cytokine IL-1 receptor antagonists and suppressors of cytokine signaling 3, their influence on other immune functions was limited to the specific phage. A protolerogenic and anti-inflammatory cytokine IL-10 was induced by all tested Pseudomonas phages, but not by a staphylococcal phage. On the other hand, the latter phage caused TNF\u03b1, while only two of the four Pseudomonas phages studied had similar effects. Moreover, the TLR4 gene was exclusively downregulated by a Pseudomonas PMN phage, indicating its anti-inflammatory action (TLR4 activation mediates the secretion of pro-inflammatory cytokines) [13]. The diversity of phage action on the immune system was also confirmed by more recent data showing that a filamentous Pseudomonas Pf phage inhibits TNF production and phagocytosis, while Escherichia coli filamentous Fd phage has no such effects [8]. Furthermore, our data suggest that both T4 coliphage and A5\/80 Staphylococcus aureus phage significantly reduce the expression of human adenovirus genes, but viral DNA synthesis is only inhibited by T4 coliphage [14]. In addition, there is evidence that temperate and lytic phages may differ in their effect on the immune system [8]. Prophages are indeed the main factor for bacterial heterogeneity of the immune system between strains, which manifests as variation of the adaptive T- and B-cell immune responses of human lymphocytes in vitro to S. aureus and Streptococcus pyogenes [15]. <\/em><\/p>\n

Immunomodulatory and anti-inflammatory effects of phages can also be cell- and tissue-specific. Intranasal administration of 536_P1 (but not LM33-P1) coliphage in mice with experimental pneumonia led to an increase in antiviral lung cytokines and chemokines. Neither phage caused changes in blood cytokine\/chemokine levels, which also suggests that phage effects on the immune system can have different manifestations in different compartments of the body [16]. The ability of the phage to mediate tissue-specific activity is confirmed by Pincus et al. [17], where the staphylococcal phage did not induce pro-inflammatory cytokines in human peripheral blood mononuclear cells but was able to induce IFN-\u03b3 in human keratinocytes. Furthermore, we have shown that A5\/80 staphylococcal phage increases IL-2 expression in the A549 cell line [18]; an activity not yet reported for phage action on other cell types in in vitro studies. An increase in serum IL-2 levels in response to phage administration was also recently reported in mice treated with Acinetobacter baumannii phages, but their cellular source is unknown [19].<\/em><\/p>\n

As already mentioned, recent data suggest that phages can be internalized by mammalian cells and undergo a large number of transcytoses via intestinal epithelial cells, while immune cells also internalize phages, particularly dendritic cells (DCs), monocytes, and B-cells [7,8]. We recently described a clear phage-dependent stimulation of the Hsp72 gene [18]. This induction of a known cellular chaperone may be a mechanism to protect cells undergoing transcytosis from potential damage by intracellular phages. Furthermore, Hsp72 is known to reduce T-cell proliferation and cytokine secretion, independently of the stimuli used, and inhibits the DC’s ability to stimulate allogeneic T-cells. This may suggest that Hsp72 could be used as an immunomodulator [20]. It has also been shown to suppress experimental arthritis in rats [21]. We have reported that phages can inhibit the development of collagen-induced arthritis in mice, an experimental model of rheumatoid arthritis [22]. Interestingly, Hsp72 has also been shown to suppress arthritis in this model [23]. It is very likely that the phage-dependent induction of Hsp72 is at least partially responsible for the inhibition of phage-induced abnormal immune responses (including autoimmunity and hyperinflammation) [24]. <\/em>
\nPhage interactions with immune cells may depend on specific phage receptors that enable these interactions. Currently, little data is available on the nature of such receptors. Pruzzo et al. [25] proposed that coliphages T3 and T7 could attach to epithelial cells with their receptors for Klebsiella pneumoniae. Our hypothesis pointed to a Lys-Gly-Asp (KGD) sequence present in one of the T4 phage capsid proteins as a potential ligand for cellular integrin receptors [24]. Lehti et al. showed that E. coli phage can recognize and bind neuroblastoma cells that have polysialic acid on their surface [26]. If polysialic acid is indeed a ligand for receptors of some phages, it could enable these phages to bind to immune cells, as the presence of polysialic acid has also been demonstrated on human DCs, NK cells, and a subpopulation of T-cells [27,28]. Thus, it is likely that different phages can use different cellular ligands to bind to and transcytose into target cells, including those of the immune system. Notably, even a single amino acid substitution in a phage capsid protein can achieve a >1000-fold improvement in phage survival in mouse circulation, which likely reflects altered interactions between phages and phagocytes (and perhaps other cells that endocytose phages) [29].<\/em><\/p>\n

Phages not only target specific bacteria but can also \u2013 at least partially \u2013 induce phage-specific immune responses. These results open up an exciting new field for further research into the significance of such responses for health and disease. Furthermore, these data suggest that a particular phage could be optimally selected for use in PT from various phage strains that recognize a specific bacterium, taking into account both its antibacterial activity and the nature of the immune response it can elicit. This is important for patients with immunodeficiencies, autoimmunity, allograft recipients, etc., who \u2013 depending on the nature of their condition \u2013 require immune stimulation or immunosuppression. Naturally, further research in this area can pave the way for the use of specific phages in immunomodulation.”<\/em><\/p>\n

Translation of the source: https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6802706\/<\/p>\n

Phage-specific diverse effects of bacterial viruses on the immune system
\nAndrzej G\u00f3rski, Ryszard Mi\u0119dzybrodzki, Ewa Jo\u0144czyk-Matysiak, Maciej \u017baczek, and Jan Borysowski<\/p>\n","protected":false},"excerpt":{"rendered":"

“With the increasing threat of antibiotic resistance, interest in phage therapy (PT) as a potential solution to this crisis has rapidly grown. Recently, several reports have been published describing successful treatment of patients with life-threatening antibiotic-resistant bacterial infections, including lung transplant recipients and treatment with genetically modified phages. Furthermore, the first PT center was opened […]<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_bbp_topic_count":0,"_bbp_reply_count":0,"_bbp_total_topic_count":0,"_bbp_total_reply_count":0,"_bbp_voice_count":0,"_bbp_anonymous_reply_count":0,"_bbp_topic_count_hidden":0,"_bbp_reply_count_hidden":0,"_bbp_forum_subforum_count":0,"footnotes":""},"categories":[253],"tags":[],"class_list":["post-8549","post","type-post","status-publish","format-standard","hentry","category-bacteriophages"],"jetpack_featured_media_url":"","_links":{"self":[{"href":"https:\/\/www.phage.help\/en\/wp-json\/wp\/v2\/posts\/8549","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.phage.help\/en\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.phage.help\/en\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.phage.help\/en\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/www.phage.help\/en\/wp-json\/wp\/v2\/comments?post=8549"}],"version-history":[{"count":0,"href":"https:\/\/www.phage.help\/en\/wp-json\/wp\/v2\/posts\/8549\/revisions"}],"wp:attachment":[{"href":"https:\/\/www.phage.help\/en\/wp-json\/wp\/v2\/media?parent=8549"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.phage.help\/en\/wp-json\/wp\/v2\/categories?post=8549"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.phage.help\/en\/wp-json\/wp\/v2\/tags?post=8549"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}