Within the broad range of viral and non-viral pathogens infecting cetaceans, Cetacean Morbillivirus (CeMV), Herpesvirus (HV), Brucella ceti, and Toxoplasma gondii are of special concern, due to their impact(s) on the health and conservation of free-ranging cetacean populations worldwide (1). The most \u201cparadigmatic\u201d example in this direction is represented by CeMV, which throughout the last 3 decades has caused more than 10 mass mortality outbreaks among different cetacean species and populations across the globe (2, 3)

Centelleghe, Cinzia

Di Guardo, Giovanni

Mazzariol, Sandro

Frontiers in Immunology

English

Giovanni Di Guardo

Cinzia Centelleghe

Sandro Mazzariol

Directory of Open Access Journals

OPINIONpublished: 28 November 2018doi: 10.3389/fimmu.2018.02815Frontiers in Immunology | www.frontiersin.org 1 November 2018 | Volume 9 | Article 2815Edited by:Fabrizio Ceciliani,Università degli Studi di Milano, ItalyReviewed by:Francisco Javier Aznar,University of Valencia, Spain*Correspondence:Giovanni Di Guardogdiguardo@unite.itSpecialty section:This article was submitted toComparative Immunology,a section of the journalFrontiers in ImmunologyReceived: 14 September 2018Accepted: 14 November 2018Published: 28 November 2018Citation:Di Guardo G, Centelleghe C andMazzariol S (2018) CetaceanHost-Pathogen Interaction(s): CriticalKnowledge Gaps.Front. Immunol. 9:2815.doi: 10.3389/fimmu.2018.02815Cetacean Host-PathogenInteraction(s): Critical KnowledgeGapsGiovanni Di Guardo 1*, Cinzia Centelleghe 2 and Sandro Mazzariol 21 Faculty of Veterinary Medicine, University of Teramo, Teramo, Italy, 2Department of Comparative Biomedicine and FoodScience, University of Padua, Padova, ItalyKeywords: cetaceans, Cetacean Morbillivirus, Herpesvirus, Brucella ceti, Toxoplasma gondii, host-pathogeninteraction, cell receptors, immunotoxic pollutantsWithin the broad range of viral and non-viral pathogens infecting cetaceans,CetaceanMorbillivirus(CeMV),Herpesvirus (HV), Brucella ceti, and Toxoplasma gondii are of special concern, due to theirimpact(s) on the health and conservation of free-ranging cetacean populations worldwide (1). Themost “paradigmatic” example in this direction is represented by CeMV, which throughout the last3 decades has caused more than 10 mass mortality outbreaks among different cetacean species andpopulations across the globe (2, 3).Cetaceans live permanently in the marine environment, a peculiar feature differentiating themfrom pinnipeds, that are also susceptible to morbilliviral infections. This has been clearly shown,for instance, by the dramatic Phocine/Phocid Distemper Virus (PDV) and Canine Distemper Virus(CDV) epidemics among North Sea common seals (Phoca vitulina) and Lake Bajkal seals (Pusasiberica) as well as Caspian seals (Pusa caspica), respectively (4). Due to their “in-water-only” life,stranded cetaceans play a key role as “sentinels” (potentially) able to “recapitulate” the “naturalhistory, evolution, ecology, epidemiology, and encounters” of infectious noxae, on one side, andcetacean hosts, on the other. Consequently, based upon their crucial relevance as “health andconservation biomonitors” for their increasingly threatened “conspecifics and heterospecifics”living in the open sea, a detailed post-mortem examination of stranded cetaceans on behalf ofspecifically trained veterinarians is mandatory!These concepts are nicely exemplified by the motto “Hic est locus ubi mors gaudet succurrerevitae.” This phrase, written in the nineteenth century by Luciano Armanni—the co-discovererof “Armanni-Ebstein Diabetic Nephropathy” (5) -, stands at the entrance of the autopsy room of“Ospedale degli Incurabili” in Naples, Italy. Literally translated, it means “This is the place wheredeath is pleased to support life.”Taking into consideration all the above, we believe there are still a number of critical “knowledgegaps” regarding “cetacean host(s)-pathogen(s) interaction(s),” with special emphasis on the 4 hereindealt infectious noxae and, most likely, also in relation to any other pathogen infecting wildcetaceans.These “knowledge-deficient areas” may be identified as follows: (1) characterization of thecell receptor(s) allowing infection; (2) interaction(s) and effects of chemical pollutants on theexpression levels of the aforementioned cell receptors; (3) pathogenetic evolution of the concernedinfections in T helper 1 (Th1)-dominant versus (vs.) Th2-dominant cetacean individuals; (4) effectsof pregnancy-associated immune status on the infectious potential of the herein dealt pathogens;(5) usefulness of cetaceans and their pathogens as models for human disease.The present Opinion Article, after a brief introduction on these 5 issues, will critically addresseach of the aforementioned knowledge gaps.Di Guardo et al. Host-Pathogen Interaction in CetaceansAs far as issue (1) is specifically concerned, CeMV, HV, B.ceti, and T. gondii may infect several cetacean hosts, with thelatter 2 agents also carrying a zoonotic potential (1). Sincedifferent tissues from susceptible cetaceans may be colonized bythe 4 herein dealt pathogens (1, 2), a detailed characterizationof the cell receptor(s) allowing their entry into (and subsequentshedding from) host’s tissues would be of paramount relevance.In this respect, as with other animal and human morbilliviruses,the lymphotropic behavior typically displayed by CeMV isspecified by the lymphoid cell receptor “Signaling LymphocyteActivation Molecule” (SLAM/CD150) (2). Notwithstanding theabove, the cell receptor(s) targeted by this lympho-epithelio-neurotropic virus within the central nervous system (CNS) fromsusceptible cetacean hosts is/are still unknown (6, 7).Noteworthy, striped dolphins (Stenella coeruleoalba)infected by Dolphin Morbillivirus (DMV, a CeMV strain)may occasionally develop a peculiar, “brain-only” form ofinfection sharing neuropathologic similarities with “SubacuteSclerosing Panencephalitis” (SSPE) and “Old Dog Encephalitis”(ODE) in Measles Virus (MeV)-infected humans and CDV-infected canines, respectively (2, 8–10). Despite the recentcharacterization of the neuronal and non-neuronal cellpopulations residing in the brain from striped dolphinsaffected by such neuropathy (11), the receptor(s) allowing viralpersistence and spread within their brains—as well as in thosefrom SSPE-afflicted patients and ODE-affected dogs—is/are alsoundetermined (6, 7, 12).Identical considerations apply to HV, B. ceti, and T. gondii,provided that the cell receptor(s) allowing their entry into andsubsequent dissemination throughout cetacean hosts’ tissueshave not been yet identified, to the best of our knowledge.Making specific reference to B. ceti, the host’s cellular prionprotein (PrPC) has been recently hypothesized to serve as aneuronal cell receptor for this zoonotic microorganism causingfatal neurobrucellosis in striped dolphins (13). Indeed, PrPChad been previously recognized as a receptor for B. abortusheat shock protein (HSP)60—a member of the GroEL familyof chaperonins—on murine macrophages, thereby allowingbacterial internalization and establishment of B. abortus infectioninside these cells (14).As far as concerns issue (2), it is well established thata wide range of persistent environmental pollutants mayheavily accumulate in cetacean tissues, especially in thoseof “top predators” like dolphins and other Odontocetes,with simultaneous “biomagnification” processes additionallyoccurring in most cases (15). Many of these pollutants, asin the case of lipophilic polychlorinated biphenyls (PCBs),dioxins and dioxin-like substances, along with methylmercury(MeHg), have also been shown to exert powerful immunotoxiceffects (16). Notwithstanding the above, we are not awareof any study investigating the relationship(s), if any, betweenpollutant-related immunotoxicity, on one side, and the tissueexpression profiles, on the other, of given cell receptors (e.g.,SLAM/CD150) for highly immunosuppressive agents like CeMV(6). This should be regarded as another critical knowledge gapwithin the general framework of “cetacean host(s)-pathogen(s)interaction dynamics.” Within such context, the growingconcerns over the exponentially increasing plastic pollutionof oceans and seas across the entire globe should be alsotaken into account. As a matter of fact, relevant health- andconservation-related issues arise for fish, birds and aquaticmammals, due to their prolonged exposure tomicro-nanoplasticsthrough the marine food web(s). Furthermore, the documentedroles of “plastic debris” as an “attractor and concentrator”for many persistent pollutants like PCBs, dioxins and otherorganochlorine (OC) and non-OC compounds (15), as wellas for a huge number of invertebrate organisms (17), woulddeserve special consideration. In this respect, plastics/micro-nanoplastics-based “rafts” have been recently hypothesized toplay a role also in the ecology and epidemiology of T. gondiiinfection (18). This could be of interest, provided that theScientific Community has not yet clarified by which modalitiesand dynamics striped dolphins and other typically “pelagic” or“offshore” cetaceans may acquire an “oro-faecally transmittedinfection” characterized by a “land-to-sea flow,” as in thecase of that caused by the zoonotic protozoan T. gondii(19).As far as issue (3) is specifically concerned, among the manylessons provided by natural history of Human ImmunodeficiencyVirus (HIV) infection in mankind, we have learned thatTh2-dominant patients are much more prone than theirTh1-dominant “counterparts” to develop “full-blown AIDS”(“Acquired Immunodeficiency Syndrome”) in the time course ofHIV infection (20). In this respect, while in recent years wehave also learned quite a bit on the pathogenetic evolution ofother human and animal viral and non-viral infections in Th1-dominant vs. Th2-dominant individuals, we are unaware, on thecontrary, of any published reports dealing with the pathogeneticbehavior of CeMV infection—as well as of HV, T. gondii,and B. ceti infections—among Th1-dominant vs. Th2-dominantcetacean hosts.This could of relevance also in relation to issue (4), given thata reduced efficiency of host’s immune response is physiologicallyobserved during pregnancy (21). Indeed, several cases of DMVinfection have been recently described both in newborns andin cetacean fetuses (6, 22–24). This concern and its relatedknowledge gap are additionally amplified by the documentedoccurrence of cases of DMV infection in cetacean species—mainly from the Western Mediterranean Sea—into which thevirus has apparently “jumped,” most likely as the result of recent“spillovers” from DMV-infected striped dolphins (22–24).Finally, with specific reference to the last of the 5 hereindealt issues, the potential role of cetaceans as “models for humandisease” should be also taken into account (25). In fact, asrecently reported for Alzheimer’s disease-related neuropathologyin striped and bottlenose dolphins (Tursiops truncatus) (26, 27),and as previously described for the aforementioned “brain-only” forms of DMV infection among striped dolphins (6, 8–10), cetaceans and—more in general—aquatic mammals couldserve as valuable “models” also in “Comparative Immunology andImmunopathology.”This could apply, in parallel with the herein dealt “host(s)-pathogen(s) interaction dynamics,” also to the “ontogeny” and“evolutionary phylogeny” of cetaceans’ immune response as wellFrontiers in Immunology | www.frontiersin.org 2 November 2018 | Volume 9 | Article 2815Di Guardo et al. Host-Pathogen Interaction in Cetaceansas to further key issues like “immune tolerance,” “autoimmunity,”and “immune surveillance against neoplasia,” just to cite a few.In conclusion, deepening our understanding of“host(s)-pathogen(s) interaction(s)” in cetaceans and,more broadly, in marine mammals, may provide not onlya very useful and insightful “set of tools” to monitorand protect their increasingly threatened health andconservation, but also a reliable and precious sourceof knowledge highlighting the simultaneous role ofcetaceans as putative “models for human (and animal)disease” as well as for “Comparative Immunology andImmunopathology.”AUTHOR CONTRIBUTIONSGDG wrote the first draft as well as the first revision’s draft ofthe present Opinion Article, to be included in the Research TopicComparative Immunology of Marine Mammals, with CC and SMsubsequently integrating and providing a thorough and criticalrevision of both the aforementioned manuscript’s drafts.REFERENCES1. Van Bressem MF, Raga JA, Di Guardo G, Jepson PD, Duignan PJ, SiebertU, et al. Emerging infectious diseases in cetaceans worldwide and thepossible role of environmental stressors. Dis Aquat Organ. (2009) 86:143–57.doi: 10.3354/dao021012. Van Bressem MF, Duignan PJ, Banyard A, Barbieri M, Colegrove KM, DeGuise S, et al.CetaceanMorbillivirus: current knowledge and future directions.Viruses (2014) 6:5145–81. doi: 10.3390/v61251453. Jo WK, Osterhaus AD, Ludlow M. Transmission of morbilliviruses withinand among marine mammal species. Curr Opin Virol. (2018) 28:133–41.doi: 10.1016/j.coviro.2017.12.0054. Duignan PJ, Van BressemM-F, Baker JD, Barbieri M, Colegrove KM, De GuiseS, et al. Phocine Distemper Virus: current knowledge and future directions.Viruses (2014) 6:5093–134. doi: 10.3390/v61250935. Ritchie S,WaughD. The pathology of Armanni-Ebstein diabetic nephropathy.Am J Pathol. (1957) 33:1035–57.6. Di Guardo G, Mazzariol S. Cetacean morbillivirus-associatedpathology: knowns and unknowns. Front Microbiol. (2016) 7:112.doi: 10.3389/fmicb.2016.001127. Di Guardo G, Giacominelli-Stuffler R, Mazzariol S. Commentary: SLAM-and Nectin-4-independent noncytolytic spread of Canine Distemper Virus inastrocytes. Front Microbiol. (2016) 7:2011. doi: 10.3389/fmicb.2016.020118. Domingo M, Vilafranca M, Visa J, Prats N, Trudgett A, Visser I. Evidence forchronicMorbillivirus infection in the Mediterranean striped dolphin (Stenellacoeruleoalba). Vet Microbiol. (1995) 44:229–39.9. Di Guardo G, Cocumelli C, Scholl F, Di Francesco CE, Speranza R, PennelliM, et al. Morbilliviral encephalitis in a striped dolphin Stenella coeruleoalbacalf from Italy. Dis Aquat Organ. (2011) 95:247–51. doi: 10.3354/dao0235510. Soto S, Alba A, Ganges L, Vidal E, Raga JA, Alegre F, et al. Post-epizootic chronic Dolphin Morbillivirus infection in Mediterranean stripeddolphins Stenella coeruleoalba. Dis Aquat Organ. (2011) 96:187–94.doi: 10.3354/dao0238711. Lucá R, Giacominelli-Stuffler R, Mazzariol S, Roperto S, Cocumelli C, DiGuardo G. Neuronal and astrocytic involvement in striped dolphins (Stenellacoeruleoalba) with morbilliviral encephalitis. Acta Virol. (2017) 61:495–7.doi: 10.4149/av_2017_41412. Alves L, Khosravi M, Avila M, Ader-Ebert N, Bringolf F, Zurbriggen A, et al.SLAM- and nectin-4-independent noncytolytic spread of canine distempervirus in astrocytes. J Virol. (2015) 89:5724–33. doi: 10.1128/JVI.00004-1513. Di Guardo G, Mazzariol S. Commentary: advancement of knowledgeof brucella over the past 50 years. Front Vet Sci. (2015) 2:27.doi: 10.3389/fvets.2015.0002714. Watarai M, Kim S, Erdenebaatar J, Makino S, Horiuchi M, Shirahata T, et al.Cellular prion protein promotes Brucella infection into macrophages. J ExpMed. (2003) 198:5–17. doi: 10.1084/jem.2002198015. FossiMC, Panti C, BainiM, Lavers JL. A review of plastic-associated pressures:cetaceans of the mediterranean sea and Eastern Australian shearwaters as casestudies. Front Mar Sci. (2018) 5:173. doi: 10.3389/fmars.2018.0017316. Desforges JP, Sonne C, Levin M, Siebert U, De Guise S, Dietz R. Immunotoxiceffects of environmental pollutants in marine mammals. Environ Int. (2016)86:126–39. doi: 10.1016/j.envint.2015.10.00717. Carlton JT, Chapman JW, Geller JB, Miller JA, Carlton DA, McCullerMI, et al. Tsunami-driven rafting: transoceanic species dispersal andimplications for marine biogeography. Science (2017) 357:1402–6.doi: 10.1126/science.aao149818. Di Guardo G, Mazzariol S. Tsunami and microbial pathogens (eLetter).Science 357 (2017). Available online at: https://science.sciencemag.org/content/357/6358/1402/tab-e-letters19. Di Guardo G, Mazzariol S. Toxoplasma gondii: clues from strandeddolphins. Vet Pathol. (2013) 50:737. doi: 10.1177/030098581348681620. Romagnani S. T-cell subsets (Th1 versus Th2). Ann Allergy Asthma Immunol.(2000) 85:9–18. doi: 10.1016/S1081-1206(10)62426-X21. Sykes L, MacIntyre DA, Yap XJ, Teoh TG, Bennett PR. The Th1:Th2dichotomy of pregnancy and preterm labour. Mediators Inflamm. (2012)2012:967629. doi: 10.1155/2012/96762922. Mazzariol S, Centelleghe C, Beffagna G, Povinelli M, Terracciano G,Cocumelli C, et al. Mediterranean fin whales (Balaenoptera physalus)threatened by Dolphin Morbillivirus. Emerg Infect Dis. (2016) 22:302–5.doi: 10.3201/eid2202.15-088223. Centelleghe C, Beffagna G, Palmisano G, Franzo G, Casalone C, Pautasso A,et al. Dolphin Morbillivirus in a Cuvier’s Beaked Whale (Ziphius cavirostris),Italy. Front Microbiol. (2017) 8:111. doi: 10.3389/fmicb.2017.0011124. Mazzariol S, Centelleghe C, Di Provvido A, Di Renzo L, Cardeti G, CersiniA, et al. Dolphin Morbillivirus associated with a mass stranding of spermwhales, Italy. Emerg Infect Dis. (2017) 23:144–6. doi: 10.3201/eid2301.16023925. Di Guardo G. Cetaceans, models for human disease? Res Vet Sci. (2018)119:43–4. doi: 10.1016/j.rvsc.2018.05.01226. Gunn-Moore D, Kaidanovich-Beilin O, Gallego Iradi MC, Gunn-Moore F,Lovestone S. Alzheimer’s disease in humans and other animals: A consequenceof postreproductive life span and longevity rather than aging. AlzheimersDement. (2018) 14:195–204. doi: 10.1016/j.jalz.2017.08.01427. Di Guardo G. Alzheimer’s disease, cellular prion protein, and dolphins.Alzheimers Dement. (2018) 14:259–60. doi: 10.1016/j.jalz.2017.12.002Conflict of Interest Statement: The authors declare that the research wasconducted in the absence of any commercial or financial relationships that couldbe construed as a potential conflict of interest.Copyright © 2018 Di Guardo, Centelleghe and Mazzariol. This is an open-accessarticle distributed under the terms of the Creative Commons Attribution License (CCBY). The use, distribution or reproduction in other forums is permitted, providedthe original author(s) and the copyright owner(s) are credited and that the originalpublication in this journal is cited, in accordance with accepted academic practice.No use, distribution or reproduction is permitted which does not comply with theseterms.Frontiers in Immunology | www.frontiersin.org 3 November 2018 | Volume 9 | Article 2815

Cetacean Host-Pathogen Interaction(s): Critical Knowledge Gaps

Within the broad range of viral and non-viral pathogens infecting cetaceans, Cetacean Morbillivirus (CeMV), Herpesvirus (HV), Brucella ceti, and Toxoplasma gondii are of special concern, due to their impact(s) on the health and conservation of free-ranging cetacean populations worldwide (1). The most “paradigmatic” example in this direction is represented by CeMV, which throughout the last 3 decades has caused more than 10 mass mortality outbreaks among different cetacean species and populations across the globe (2, 3)

Archivio istituzionale della ricerca - Università di Padova

OPINIONpublished: 28 November 2018doi: 10.3389/fimmu.2018.02815Frontiers in Immunology | www.frontiersin.org 1 November 2018 | Volume 9 | Article 2815Edited by:Fabrizio Ceciliani,Università degli Studi di Milano, ItalyReviewed by:Francisco Javier Aznar,University of Valencia, Spain*Correspondence:Giovanni Di Guardogdiguardo@unite.itSpecialty section:This article was submitted toComparative Immunology,a section of the journalFrontiers in ImmunologyReceived: 14 September 2018Accepted: 14 November 2018Published: 28 November 2018Citation:Di Guardo G, Centelleghe C andMazzariol S (2018) CetaceanHost-Pathogen Interaction(s): CriticalKnowledge Gaps.Front. Immunol. 9:2815.doi: 10.3389/fimmu.2018.02815Cetacean Host-PathogenInteraction(s): Critical KnowledgeGapsGiovanni Di Guardo 1*, Cinzia Centelleghe 2 and Sandro Mazzariol 21 Faculty of Veterinary Medicine, University of Teramo, Teramo, Italy, 2Department of Comparative Biomedicine and FoodScience, University of Padua, Padova, ItalyKeywords: cetaceans, Cetacean Morbillivirus, Herpesvirus, Brucella ceti, Toxoplasma gondii, host-pathogeninteraction, cell receptors, immunotoxic pollutantsWithin the broad range of viral and non-viral pathogens infecting cetaceans,CetaceanMorbillivirus(CeMV),Herpesvirus (HV), Brucella ceti, and Toxoplasma gondii are of special concern, due to theirimpact(s) on the health and conservation of free-ranging cetacean populations worldwide (1). Themost “paradigmatic” example in this direction is represented by CeMV, which throughout the last3 decades has caused more than 10 mass mortality outbreaks among different cetacean species andpopulations across the globe (2, 3).Cetaceans live permanently in the marine environment, a peculiar feature differentiating themfrom pinnipeds, that are also susceptible to morbilliviral infections. This has been clearly shown,for instance, by the dramatic Phocine/Phocid Distemper Virus (PDV) and Canine Distemper Virus(CDV) epidemics among North Sea common seals (Phoca vitulina) and Lake Bajkal seals (Pusasiberica) as well as Caspian seals (Pusa caspica), respectively (4). Due to their “in-water-only” life,stranded cetaceans play a key role as “sentinels” (potentially) able to “recapitulate” the “naturalhistory, evolution, ecology, epidemiology, and encounters” of infectious noxae, on one side, andcetacean hosts, on the other. Consequently, based upon their crucial relevance as “health andconservation biomonitors” for their increasingly threatened “conspecifics and heterospecifics”living in the open sea, a detailed post-mortem examination of stranded cetaceans on behalf ofspecifically trained veterinarians is mandatory!These concepts are nicely exemplified by the motto “Hic est locus ubi mors gaudet succurrerevitae.” This phrase, written in the nineteenth century by Luciano Armanni—the co-discovererof “Armanni-Ebstein Diabetic Nephropathy” (5) -, stands at the entrance of the autopsy room of“Ospedale degli Incurabili” in Naples, Italy. Literally translated, it means “This is the place wheredeath is pleased to support life.”Taking into consideration all the above, we believe there are still a number of critical “knowledgegaps” regarding “cetacean host(s)-pathogen(s) interaction(s),” with special emphasis on the 4 hereindealt infectious noxae and, most likely, also in relation to any other pathogen infecting wildcetaceans.These “knowledge-deficient areas” may be identified as follows: (1) characterization of thecell receptor(s) allowing infection; (2) interaction(s) and effects of chemical pollutants on theexpression levels of the aforementioned cell receptors; (3) pathogenetic evolution of the concernedinfections in T helper 1 (Th1)-dominant versus (vs.) Th2-dominant cetacean individuals; (4) effectsof pregnancy-associated immune status on the infectious potential of the herein dealt pathogens;(5) usefulness of cetaceans and their pathogens as models for human disease.The present Opinion Article, after a brief introduction on these 5 issues, will critically addresseach of the aforementioned knowledge gaps.Di Guardo et al. Host-Pathogen Interaction in CetaceansAs far as issue (1) is specifically concerned, CeMV, HV, B.ceti, and T. gondii may infect several cetacean hosts, with thelatter 2 agents also carrying a zoonotic potential (1). Sincedifferent tissues from susceptible cetaceans may be colonized bythe 4 herein dealt pathogens (1, 2), a detailed characterizationof the cell receptor(s) allowing their entry into (and subsequentshedding from) host’s tissues would be of paramount relevance.In this respect, as with other animal and human morbilliviruses,the lymphotropic behavior typically displayed by CeMV isspecified by the lymphoid cell receptor “Signaling LymphocyteActivation Molecule” (SLAM/CD150) (2). Notwithstanding theabove, the cell receptor(s) targeted by this lympho-epithelio-neurotropic virus within the central nervous system (CNS) fromsusceptible cetacean hosts is/are still unknown (6, 7).Noteworthy, striped dolphins (Stenella coeruleoalba)infected by Dolphin Morbillivirus (DMV, a CeMV strain)may occasionally develop a peculiar, “brain-only” form ofinfection sharing neuropathologic similarities with “SubacuteSclerosing Panencephalitis” (SSPE) and “Old Dog Encephalitis”(ODE) in Measles Virus (MeV)-infected humans and CDV-infected canines, respectively (2, 8–10). Despite the recentcharacterization of the neuronal and non-neuronal cellpopulations residing in the brain from striped dolphinsaffected by such neuropathy (11), the receptor(s) allowing viralpersistence and spread within their brains—as well as in thosefrom SSPE-aﬄicted patients and ODE-affected dogs—is/are alsoundetermined (6, 7, 12).Identical considerations apply to HV, B. ceti, and T. gondii,provided that the cell receptor(s) allowing their entry into andsubsequent dissemination throughout cetacean hosts’ tissueshave not been yet identified, to the best of our knowledge.Making specific reference to B. ceti, the host’s cellular prionprotein (PrPC) has been recently hypothesized to serve as aneuronal cell receptor for this zoonotic microorganism causingfatal neurobrucellosis in striped dolphins (13). Indeed, PrPChad been previously recognized as a receptor for B. abortusheat shock protein (HSP)60—a member of the GroEL familyof chaperonins—on murine macrophages, thereby allowingbacterial internalization and establishment of B. abortus infectioninside these cells (14).As far as concerns issue (2), it is well established thata wide range of persistent environmental pollutants mayheavily accumulate in cetacean tissues, especially in thoseof “top predators” like dolphins and other Odontocetes,with simultaneous “biomagnification” processes additionallyoccurring in most cases (15). Many of these pollutants, asin the case of lipophilic polychlorinated biphenyls (PCBs),dioxins and dioxin-like substances, along with methylmercury(MeHg), have also been shown to exert powerful immunotoxiceffects (16). Notwithstanding the above, we are not awareof any study investigating the relationship(s), if any, betweenpollutant-related immunotoxicity, on one side, and the tissueexpression profiles, on the other, of given cell receptors (e.g.,SLAM/CD150) for highly immunosuppressive agents like CeMV(6). This should be regarded as another critical knowledge gapwithin the general framework of “cetacean host(s)-pathogen(s)interaction dynamics.” Within such context, the growingconcerns over the exponentially increasing plastic pollutionof oceans and seas across the entire globe should be alsotaken into account. As a matter of fact, relevant health- andconservation-related issues arise for fish, birds and aquaticmammals, due to their prolonged exposure tomicro-nanoplasticsthrough the marine food web(s). Furthermore, the documentedroles of “plastic debris” as an “attractor and concentrator”for many persistent pollutants like PCBs, dioxins and otherorganochlorine (OC) and non-OC compounds (15), as wellas for a huge number of invertebrate organisms (17), woulddeserve special consideration. In this respect, plastics/micro-nanoplastics-based “rafts” have been recently hypothesized toplay a role also in the ecology and epidemiology of T. gondiiinfection (18). This could be of interest, provided that theScientific Community has not yet clarified by which modalitiesand dynamics striped dolphins and other typically “pelagic” or“offshore” cetaceans may acquire an “oro-faecally transmittedinfection” characterized by a “land-to-sea flow,” as in thecase of that caused by the zoonotic protozoan T. gondii(19).As far as issue (3) is specifically concerned, among the manylessons provided by natural history of Human ImmunodeficiencyVirus (HIV) infection in mankind, we have learned thatTh2-dominant patients are much more prone than theirTh1-dominant “counterparts” to develop “full-blown AIDS”(“Acquired Immunodeficiency Syndrome”) in the time course ofHIV infection (20). In this respect, while in recent years wehave also learned quite a bit on the pathogenetic evolution ofother human and animal viral and non-viral infections in Th1-dominant vs. Th2-dominant individuals, we are unaware, on thecontrary, of any published reports dealing with the pathogeneticbehavior of CeMV infection—as well as of HV, T. gondii,and B. ceti infections—among Th1-dominant vs. Th2-dominantcetacean hosts.This could of relevance also in relation to issue (4), given thata reduced efficiency of host’s immune response is physiologicallyobserved during pregnancy (21). Indeed, several cases of DMVinfection have been recently described both in newborns andin cetacean fetuses (6, 22–24). This concern and its relatedknowledge gap are additionally amplified by the documentedoccurrence of cases of DMV infection in cetacean species—mainly from the Western Mediterranean Sea—into which thevirus has apparently “jumped,” most likely as the result of recent“spillovers” from DMV-infected striped dolphins (22–24).Finally, with specific reference to the last of the 5 hereindealt issues, the potential role of cetaceans as “models for humandisease” should be also taken into account (25). In fact, asrecently reported for Alzheimer’s disease-related neuropathologyin striped and bottlenose dolphins (Tursiops truncatus) (26, 27),and as previously described for the aforementioned “brain-only” forms of DMV infection among striped dolphins (6, 8–10), cetaceans and—more in general—aquatic mammals couldserve as valuable “models” also in “Comparative Immunology andImmunopathology.”This could apply, in parallel with the herein dealt “host(s)-pathogen(s) interaction dynamics,” also to the “ontogeny” and“evolutionary phylogeny” of cetaceans’ immune response as wellFrontiers in Immunology | www.frontiersin.org 2 November 2018 | Volume 9 | Article 2815Di Guardo et al. Host-Pathogen Interaction in Cetaceansas to further key issues like “immune tolerance,” “autoimmunity,”and “immune surveillance against neoplasia,” just to cite a few.In conclusion, deepening our understanding of“host(s)-pathogen(s) interaction(s)” in cetaceans and,more broadly, in marine mammals, may provide not onlya very useful and insightful “set of tools” to monitorand protect their increasingly threatened health andconservation, but also a reliable and precious sourceof knowledge highlighting the simultaneous role ofcetaceans as putative “models for human (and animal)disease” as well as for “Comparative Immunology andImmunopathology.”AUTHOR CONTRIBUTIONSGDG wrote the first draft as well as the first revision’s draft ofthe present Opinion Article, to be included in the Research TopicComparative Immunology of Marine Mammals, with CC and SMsubsequently integrating and providing a thorough and criticalrevision of both the aforementioned manuscript’s drafts.REFERENCES1. 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The use, distribution or reproduction in other forums is permitted, providedthe original author(s) and the copyright owner(s) are credited and that the originalpublication in this journal is cited, in accordance with accepted academic practice.No use, distribution or reproduction is permitted which does not comply with theseterms.Frontiers in Immunology | www.frontiersin.org 3 November 2018 | Volume 9 | Article 2815

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Cetacean Host-Pathogen Interaction(s): Critical Knowledge Gaps

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