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HYPOTHESIS AND THEORY article

Front. Immunol., 23 March 2021
Sec. Nutritional Immunology
This article is part of the Research Topic Coronavirus Disease (COVID-19): Diet, Inflammation and Nutritional Status View all 29 articles

Bovine Coronavirus Immune Milk Against COVID-19

  • Department of Animal Health, University of Cordoba, Córdoba, Spain

After a year of evolution of the SARS-CoV-2 epidemic, there is still no specific effective treatment for the disease. Although the majority of infected people experience mild disease, some patients develop a serious disease, especially when other pathologies concur. For this reason, it would be very convenient to find pharmacological and immunological mechanisms that help control SARS-CoV-2 infection. Since the COVID-19 and BCoV viruses are very close phylogenetically, different studies demonstrate the existence of cross-immunity as they retain shared epitopes in their structure. As a possible control measure against COVID-19, we propose the use of cow’s milk immune to BCoV. Thus, the antigenic recognition of some highly conserved structures of viral proteins, particularly M and S2, by anti-BCoV antibodies present in milk would cause a total or partial inactivation of SARS-COV-2 (acting as a particular vaccine) and be addressed more easily by GALT’s highly specialized antigen-presenting cells, thus helping the specific immune response.

Introduction

COVID-19 is a severe human pandemic caused by the SARS-CoV-2 virus. Since there is currently no specific treatment for severe cases, it is critical to find immune mechanisms and strategies to help control the disease. We propose the use of heterologous passive immunity using Bovine Coronavirus immune milk (BIM) as an immunostimulant therapy to control SARS-CoV-2 infection, helping to activate the intestinal immune system.

The coronaviruses were initially classified according to their antigenic characteristics into three serological groups (1), known as Groups 1, 2, and 3, which were later renamed as the new genera Alphacoronavirus, Betacoronavirus, and Gammacoronavirus, respectively (2). Based on their phylogenetic relationships and genomic structures, the Betacoronavirus genus now contains five lines or subgenera, including the Sarbecovirus (which includes SARS-CoV and SARS-CoV-2), Merbecovirus (MERS-CoV), and Embecovirus subgenera.

Notable among the embecoviruses are HCoV-OC43 (OC43), which causes a mild human endemic respiratory infection, and Bovine Coronavirus (BCoV). These are two different biotypes of the same species, since the human virus probably evolved from strains of the bovine coronavirus that jumped the species barrier and caused sustained infection in humans (3). BCoV and OC43 share a global nucleotide identity of 96% (4); in contrast, the SARS-CoV-2 genes shared less than 80% nucleotide sequence identity to other Sarbecovirus as SARS-CoV, and about 50% to MERS-CoV (5). Viral seroneutralization techniques show that there is a close antigenic relationship between BCoV and OC43 viruses (6).

Structurally, BCoV (also OC43) is an enveloped virus composed of five structural proteins: the spike glycoprotein (S), the envelope (E) protein, the membrane (M) protein, the nucleocapsid (N) protein, and the hemagglutinin-esterase (HE) protein. The SARS-CoV-2 structure is very similar to the other members of Family Coronaviridae; also contains four structural proteins: S, E, M, and N proteins (5), but it lacks the HE protein.

To attach to host cells, BCoV uses 5-N-acetyl-9-O-acetylneuraminic acid as the preferred receptor to cellular binding (7) whereas SARS-CoV-2 binding angiotensin-converting enzyme receptor (5). Then, the fusion peptide is activated triggering the fusion of viral particle to cellular membrane. The described mechanism allows the virus to infect the host cells.

Cross-Immune Reactivity Among Betacoronaviruses

The most important immune response generated by coronaviruses is produced against S protein, since it is widely exposed on the viral surface and is an immunodominant structure. S protein is a large class I fusion protein consists of S1 subunit (S1) that contains, among other epitopes the receptor binding domain (RBD), and S2 subunit (S2) that mediates viral membrane fusion (8) contains conserved regions that are necessary for function: the fusion peptide and two conserved repeats (9, 10).

Transmembrane M protein is the most abundant structural protein and is highly conserved among the coronaviruses, but their function is not clearly understood (11). Different M protein epitopes elicit a detectable immune response in the serum of SARS and COVID-19 patients (12, 13). The OC43 M protein is an antagonist of the host antiviral defenses interfering different immune systems (14) and SARS-CoV-2 M protein plays similar effects disabling antiviral signaling cascade (15).

The viral N protein is highly conserved maintaining antigenic cross-reactivity among some coronavirus species, but no between BCoV and SARS-CoV-2 (16). The HE protein, which is not present in other betacoronaviruses (as SARS-CoV-2), enables the BCoV to bind different types of cells. The small E protein is poorly immunogenic for humoral response (17).

Cross-reactivity has been found between OC43 and SARS-CoV (18, 19), which seems to be supported by different antigenic determinants present in N, M, and S2 (a highly conserved region that is almost invariant across the betacoronaviruses), as well as between SARS-CoV and SARS-CoV-2 (20).

SARS-CoV monoclonal antibodies neutralize SARS-CoV-2 through a mechanism, yet unknown, but different from RBD interference. Likewise, alternative mechanisms of coronavirus neutralization by antibodies targeting RBD have been reported, particularly inactivation of the S protein by altering its structure in prefusion conformation (2123).

A consistent cross-reactivity, but limited cross-neutralization, has been reported between SARS-CoV-2 and other human endemic coronaviruses, including OC43 (24). In addition, recent studies have found that between 40 and 60% of people not previously exposed to SARS-CoV-2 have T helper cells (CD4+) reactive to OC43 (25). This suggests that CD4+ cells specific for endemic betacoronaviruses of the common cold may also recognize the epidemic coronavirus SARS-CoV-2. This hypothesis is reinforced by the seroconversion found in a high proportion (one in three infected) of asymptomatic human SARS-CoV-2 infections (26), some of which could be due to cross-reactivity following exposure to other human coronaviruses (particularly OC43, HCoV-229E, and HECoV viruses).

The formation of immunoglobulin G isotype (IgG) against the RBD domain of the newly emerged SARS-CoV-2 is considered essential for adequate immune protection. These specific IgGs should be absent (or at a low level) in unexposed people, nevertheless, a recent study (27) showed that IgGs reactive to the S2 subunit of SARS-CoV-2 were present in most of the unexposed subjects studied. The authors concluded that cross-reactivity with other human coronaviruses was a plausible explanation. They also found that convalescing COVID-19 patients showed a significant increase in OC43-reactive memory B cells compared with previously unexposed healthy subjects. Consequently, since everything seems to point to strong cross-reactivity between SARS-CoV-2 and OC43 at both the cellular and humoral level, it is likely also to be found with BCoV as reported previously (6). No specific cross-reactivity studies have been performed between SARS-CoV-2 and BCoV, but when the epitope sequence alignment of the SARS-CoV-2 spike proteins was analyzed, a high homology (57 to 83%) with BCoV was found (28).

The phenomenon known as antibody-dependent enhancement (ADE), in which the presence of non-neutralizing antibodies can aggravate the course of the disease, is one of the present general concerns in immunotherapy (and the development of vaccines). The pathophysiology of ADE is not yet well understood, but it appears to be closely related to low levels of neutralizing antibodies against RBD. However, it has been shown that ADE does not occur when antibodies bind to the nucleoprotein or any other structure different from RBD antigens (29).

BCoV causes specific syndromes in cattle with a very high inter- and intra-herd prevalence (30, 31) and has been associated with gastroenteritis and respiratory diseases in lactating calves (32), shipping fever in fattening calves (33) and winter diarrhea in dairy cows (34). Due to their economic, medical, and epidemiological importance, different commercial vaccines against BCoV (including live and inactivated viruses) are currently available and have shown a very good protective effect.

Immune Milk Against BCoV

Functional foods are products that not only satisfy nutritional requirements but also modulate organic functions and perform highly beneficial tasks in some diseases (35). Bovine milk and colostrum contain high levels of bioactive components, including growth factors, immunoglobulins (Igs), lactoperoxidase, lysozyme, lactoferrin, cytokines, nucleosides, vitamins, peptides, and oligosaccharides, all of them beneficial to human health (36). Hyperimmune cow’s milk has been used against human infections for a long time (37, 38). Raw and pasteurized milk can contain specific antibodies against different human pathogens (39), exerting a synergistic effect on the activity of nonspecific antimicrobial factors (40, 41). Bovine IgG is functionally active throughout the gastrointestinal tract and can prevent digestive and respiratory tract infections in humans (42).

Whole cow’s milk contains more than 30 g/L of protein, almost 1 g/L of which are immunoglobulins, which can reach more than 200 g/L in colostrum (36). IgGs present in bovine milk survive gastric exposure and resist proteolytic digestion in the stomach and intestinal tract, maintaining their active binding capacity to receptors (43). No evidence for the intestinal absorption of intact IgG has been found. In addition, the ingestion of Ig preparations obtained from serum leads to an increase in anti-inflammatory cytokines and a decrease in pro-inflammatory cytokines (44).

It was recently confirmed that SARS-CoV-2 RNA persisted longer (over a month) in the feces of infected people, mainly children, than in respiratory exudates (45, 46). This shows that the infectious period could be prolonged due to the enteric persistence of the virus, even when a person has been considered negative after a routine diagnostic test. We think that the presence of specific IgG in the intestinal lumen would help control viral excretion.

Passive immunity conferred through breast milk has a remarkable protective effect against most of the infectious diseases of animals and has been well studied in almost all coronaviruses of veterinary concern (4749). The presence of specific antibodies to SARS-CoV-2 has also been found in human breast milk (50).

Ultra-high temperature (UHT) processing is the most widely used heat treatment for the microbiological safety of milk for human consumption, but this treatment destroys the immunoglobulins present in the milk. However, pasteurization is a less aggressive heat treatment that ensures microbiological safety but also preserves most immunoglobulins in milk. Most commercial pasteurized milk from Spain contains antibodies against BCoV, probably due to the high prevalence of infection and the systematic vaccination of cattle. Nevertheless, the heat treatment process used reduces titers below 30. BIM, which we obtained by cow hyperimmunization using commercial coronavirus vaccine, contains antibodies with titers between 128 and 256 (unpublished results) and human consumption could transfer heterologous antibodies against SARS-CoV-2, thus conferring some passive immunity.

Discussion

The evolution of antibody kinetics after natural infection appears to be very similar between BCoV and SARS-CoV-2. Briefly, after infection, different antibody class (i.e., IgA, IgM, IgG) are produced directed against the different structural proteins of the virus (16). Antibodies directed against RBD are highly neutralizing, but are quite different between the two viruses, as they target different domains. In contrast, antibodies directed towards the M protein may have cross-immunity among coronaviruses, binding selectively to Fc receptors (FcRs) (51). FcRs have interesting immunological functions including phagocytosis, degranulation, antibody-dependent cellular cytotoxicity (ADCC), cytokine formation, lipid mediator, and superoxide production (52).

Animal respiratory coronaviruses often have a pneumoenteric tropism and can persist in carriers who maintain and excrete the virus in respiratory secretions, but mainly in the feces, for long periods of time, even years (30, 53). Fecal excretion has also been demonstrated in SARS-CoV-2 (45, 46) and is even more prolonged than nasal excretion. For BCoV, it has been speculated that, after initial replication, the virus spreads to the gastrointestinal tract by ingestion of large amounts of virus coated in mucous secretions, which would cause the virus to transit to the intestine, causing intestinal infection and subsequent fecal excretion (8).

Gut-associated lymphoid tissue (GALT) (Peyer’s patches, cecal and colonic patches) plays a key role in immunity since it discriminates between food antigens, commensal microorganisms, and pathogens. It should therefore have very safe mechanisms for adjusting immune response to the type of antigen that it locates. These immunoregulatory functions include mechanisms for the recruitment of lymphocytes and myeloid cells from the bloodstream to antigen sampling from surrounding tissue or the surface of the luminal epithelium, as well as others for returning activated effector lymphocytes to the bloodstream or remaining on the mucosal surface where they eliminate pathogens or reside as memory cells.

After consumption of BIM, the ingested antibodies would specifically bind to some shared antigenic structures of SARS-CoV-2. This could totally or partially inactivate the virus and facilitate the processing of SARS-CoV-2 antigens by GALT, but also the formation of immune complexes that can activate the antiviral signaling cascade (15), complement fixation, and binding to the FcRs that control humoral immunity and are essential for an adequate response to infections (52).

Bearing in mind that coronaviruses are markedly pneumoenteric viruses, GALT and other mucosa-associated lymphoid tissues are of enormous importance for the control of infection (54). The reduction in the number of active viral particles in the intestinal mucosa and the activation of other immune mechanisms in the GALT could reinforce the specific immune response against infection by SARS-CoV-2, improving the regulation of the immune system.

Thus, recognition of SARS-CoV-2 by heterologous antibodies in BIM could cause complement fixation of the immune complexes, triggering activation of any of its pathways. This would generate specific responses of neutralization, cytolysis, chemotaxis, opsonization, and others (55), as well as the activation of other immune mechanisms that would benefit immune action, such as the production of IL-10, IFN-β (56), or CD27 cells (57) (which would involve the activation, proliferation, and differentiation of B lymphocytes) or even activation of immunoglobulin class switching (58). The complexity of the cytokine network in humans makes immunomodulation essential in the control of severe COVID-19 and could be achieved by the presence of specific immunoglobulins in the GALT and gut lumen.

Considering the arguments presented above, research should be conducted, focused on exploring the effectiveness of BIM and other immune compounds (milk, milk derivatives, egg yolk, among others) in the control of COVID-19 in human patients.

Data Availability Statement

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Author Contributions

All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments

We want to thank our colleague Elvira Muñoz for her invaluable aid.

References

1. Brian DA, Baric RS. Coronavirus genome structure and replication. Curr Top Microbiol Immunol (2005) 287:1–30. doi: 10.1007/3-540-26765-4_1

CrossRef Full Text | Google Scholar

2. de Groot RJ, Baker S, Barik RS, Holmes KV. Family Coronaviridae. In: Ed: King AMQ, Adams MJ, Cartens EB, Lefkowitz EJ editors. Virus Taxonomy. Ninth Report of the International Committee on Taxonomy of Viruses. Elsevier (2012). p. 806–28. doi: 10.1016/B978-0-12-384684-6.00068-9

CrossRef Full Text | Google Scholar

3. Vijgen L, Keyaerts E, Moës E, Thoelen I, Wollants E, Lemey P, et al. Complete Genomic Sequence of Human Coronavirus OC43: Molecular Clock Analysis Suggests a Relatively Recent Zoonotic Coronavirus Transmission Event. J Virol (2005) 79(3):1595–604. doi: 10.1128/JVI.79.3.1595-1604.2005

PubMed Abstract | CrossRef Full Text | Google Scholar

4. Kin N, Miszczak F, Diancourt L, Caro V, Moutou F, Vabret A, et al. Comparative molecular epidemiology of two closely related coronaviruses, bovine coronavirus (BCoV) and human coronavirus OC43 (HCoV-OC43), reveals a different evolutionary pattern. Infect Genet Evol (2016) 40:186–91. doi: 10.1016/j.meegid.2016.03.006

PubMed Abstract | CrossRef Full Text | Google Scholar

5. Lu R, Zhao X, Li J, Niu P, Yang B, Wu H, et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor bindings. Lancet (2020) 395(10224):565–74. doi: 10.1016/S0140-6736(20)30251-8

PubMed Abstract | CrossRef Full Text | Google Scholar

6. Pedersen NC, Ward J, Mengeling WL. Antigenic relationship of the feline infectious peritonitis virus to coronaviruses of other species. Arch Virol (1978) 58(1):45–53. doi: 10.1007/BF01315534

PubMed Abstract | CrossRef Full Text | Google Scholar

7. Peng G, Xu L, Lin YL, Chen L, Pasquarella JR, Holmes KV, et al. Crystal structure of bovine coronavirus spike protein lectin domain. J Biol Chem (2012) 287(50):41931–8. doi: 10.1074/jbc.M112.418210

PubMed Abstract | CrossRef Full Text | Google Scholar

8. Saif LJ. Bovine respiratory coronavirus. Vet Clin North Am Food Anim Pract (2010) 26(2):349–64. doi: 10.1016/j.cvfa.2010.04.005

PubMed Abstract | CrossRef Full Text | Google Scholar

9. Alsaadi EA J, Jones IM. Membrane binding proteins of coronaviruses. Future Virol (2019) 14(4):275–86. doi: 10.2217/fvl-2018-0144

PubMed Abstract | CrossRef Full Text | Google Scholar

10. Prévost J, Gasser R, Beaudoin-Bussières G, Richard J, Duerr R, Laumaea A, et al. Cross-Sectional Evaluation of Humoral Responses against SARS-CoV-2 Spike. Cell Rep Med (2020) 1(7):100126. doi: 10.1016/j.xcrm.2020.100126

PubMed Abstract | CrossRef Full Text | Google Scholar

11. Schoeman D, Fielding BC. Coronavirus envelope protein: current knowledge. Virol J (2019) 16(1):69. doi: 10.1186/s12985-019-1182-0

PubMed Abstract | CrossRef Full Text | Google Scholar

12. Du L, He Y, Jiang S, Zheng BJ. Development of subunit vaccines against severe acute respiratory syndrome. Drugs Today (Barc) (2008) 44(1):63–73. doi: 10.1358/dot.2008.44.1.1131830

PubMed Abstract | CrossRef Full Text | Google Scholar

13. Thieme CJ, Anft M, Paniskaki K, Blazquez-Navarro A, Doevelaar A, Seibert FS, et al. Robust T Cell Response Toward Spike, Membrane, and Nucleocapsid SARS-CoV-2 Proteins Is Not Associated with Recovery in Critical COVID-19 Patients. Cell Rep Med (2020) 1(6):100092. doi: 10.1016/j.xcrm.2020.100092

PubMed Abstract | CrossRef Full Text | Google Scholar

14. Beidas M, Chehadeh W. Effect of Human Coronavirus OC43 Structural and Accessory Proteins on the Transcriptional Activation of Antiviral Response Elements. Intervirology (2018) 61(1):30–5. doi: 10.1159/000490566

PubMed Abstract | CrossRef Full Text | Google Scholar

15. Zheng Y, Zhuang MW, Han L, Zhang J, Nan ML, Zhan P, et al. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) membrane (M) protein inhibits type I and III interferon production by targeting RIG-I/MDA-5 signaling. Signal Transd Target Ther (2020) 5(1):299. doi: 10.1038/s41392-020-00438-7

CrossRef Full Text | Google Scholar

16. Huang AT, Garcia-Carreras B, Hitchings MDT, Yang B, Katzelnick LC, Rattigan SM, et al. A systematic review of antibody mediated immunity to coronaviruses: kinetics, correlates of protection, and association with severity. Nat Commun (2020) 11(1):4704. doi: 10.1038/s41467-020-18450-4

PubMed Abstract | CrossRef Full Text | Google Scholar

17. Zhang J, Zeng H, Gu J, Li H, Zheng L, Zou Q. Progress and Prospects on Vaccine Development against SARS-CoV-2. Vaccines (Basel) (2020) 8(2):153. doi: 10.3390/vaccines8020153

CrossRef Full Text | Google Scholar

18. Woo PC, Lau SK, Wong BH, Chan KH, Hui WT, Kwan GS, et al. False-positive results in a recombinant severe acute respiratory syndrome-associated coronavirus (SARS-CoV) nucleocapsid enzyme-linked immunosorbent assay due to HCoV-OC43 and HCoV-229E rectified by Western blotting with recombinant SARS-CoV spike polypeptide. J Clin Microbiol (2004) 42(12):5885–8. doi: 10.1128/JCM.42.12.5885-5888.2004

PubMed Abstract | CrossRef Full Text | Google Scholar

19. Che XY, Qiu LW, Liao ZY, Wang YD, Wen K, Pan YX, et al. Antigenic cross-reactivity between severe acute respiratory syndrome-associated coronavirus and human coronaviruses 229E and OC43. J Infect Dis (2005) 191(12):2033–7. doi: 10.1086/430355

PubMed Abstract | CrossRef Full Text | Google Scholar

20. Lv H, Wu NC, Tsang OT, Yuan M, Perera RAPM, Leung WS, et al. Cross-reactive Antibody Response between SARS-CoV-2 and SARS-CoV Infections. Cell Rep (2020) 31(9):107725. doi: 10.1016/j.celrep.2020.107725

CrossRef Full Text | Google Scholar

21. Wang C, Li W, Drabek D, Okba NMA, Haperen RV, Osterhaus ADME, et al. A human monoclonal antibody blocking SARS-CoV-2 infection. Nat Commun (2020) 11(1):1–6. doi: 10.1038/s41467-020-16452-w

PubMed Abstract | CrossRef Full Text | Google Scholar

22. Walls AC, Xiong X, Park YJ, Tortorici MA, Snijder J, Quispe J, et al. Unexpected Receptor Functional Mimicry Elucidates Activation of Coronavirus Fusion. Cell (2019) 176(5):1026–39.e15. doi: 10.1016/j.cell.2018.12.028

PubMed Abstract | CrossRef Full Text | Google Scholar

23. Kirchdoerfer RN, Cottrell CA, Wang N, Pallesen J, Yassine HM, Turner HL, et al. Pre-fusion structure of a human coronavirus spike protein. Nature (2016) 531(7592):118–21. doi: 10.1038/nature17200

PubMed Abstract | CrossRef Full Text | Google Scholar

24. Post N, Eddy D, Huntley C, van Schalkwyk MCI, Shrotri M, Leeman D, et al. Antibody response to SARS-CoV-2 infection in humans: A systematic review. PloS One (2020) 15(12):e0244126. doi: 10.1371/journal.pone.0244126

PubMed Abstract | CrossRef Full Text | Google Scholar

25. Grifoni A, Weiskopf D, Ramirez SI, Mateus J, Dan JM, Moderbacher CR, et al. Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans with COVID-19 Disease and Unexposed Individuals. Cell (2020) 181(7):1489–501.e15. doi: 10.1016/j.cell.2020.05.015

PubMed Abstract | CrossRef Full Text | Google Scholar

26. Pollán M, Pérez-Gómez B, Pastor-Barriuso R, Oteo J, Hernán MA, Pérez-Olmeda M, et al. Prevalence of SARS-CoV-2 in Spain (ENE-COVID): a nationwide, population-based seroepidemiological study. Lancet (2020) 396(10250):535–44. doi: 10.1016/S0140-6736(20)32266-2

PubMed Abstract | CrossRef Full Text | Google Scholar

27. Nguyen-Contant P, Embong AK, Kanagaiah P, Chaves FA, Yang H, Branche AR, et al. S Protein-Reactive IgG and Memory B Cell Production after Human SARS-CoV-2 Infection Includes Broad Reactivity to the S2 Subunit. mBio (2020) 11(5):e01991–20. doi: 10.1101/2020.07.20.213298

PubMed Abstract | CrossRef Full Text | Google Scholar

28. Tilocca B, Soggiu A, Musella V, Britti D, Sanguinetti M, Urbani A, et al. Molecular basis of COVID-19 relationships in different species: a one health perspective. Microbes Infect (2020) 22(4-5):218–20. doi: 10.1016/j.micinf.2020.03.002

PubMed Abstract | CrossRef Full Text | Google Scholar

29. Wang SF, Tseng SP, Yen CH, Yang JY, Tsao CH, Shen CW, et al. Antibody-dependent SARS coronavirus infection is mediated by antibodies against spike proteins. Biochem Biophys Res Commun (2014) 451(2):208–14. doi: 10.1016/j.bbrc.2014.07.090

PubMed Abstract | CrossRef Full Text | Google Scholar

30. Oma VS, Tråvén M, Alenius S, Myrmel M, Stokstad M. Bovine coronavirus in naturally and experimentally exposed calves; viral shedding and the potential for transmission. Virol J (2016) 13(1):1–11. doi: 10.1186/s12985-016-0555-x

PubMed Abstract | CrossRef Full Text | Google Scholar

31. Saif LJ, Jung K. Comparative Pathogenesis of Bovine and Porcine Respiratory Coronaviruses in the Animal Host Species and SARS-CoV-2 in Humans. J Clin Microbiol (2020) 58(8):e01355–20. doi: 10.1128/JCM.01355-20

PubMed Abstract | CrossRef Full Text | Google Scholar

32. Boileau MJ, Kapil S. Bovine Coronavirus Associated Syndromes. Vet Clin North Am Food Anim Pract (2010) 26(1):23–46. doi: 10.1016/j.cvfa.2009.10.003

CrossRef Full Text | Google Scholar

33. Storz J, Purdy CW, Lin X, Burrell M, Truax RE, Briggs RE, et al. Isolation of respiratory bovine coronavirus, other cytocidal viruses, and Pasteurella spp from cattle involved in two natural outbreaks of shipping fever. J Am Vet Med Assoc (2000) 216(10):1599–604. doi: 10.2460/javma.2000.216.1599

PubMed Abstract | CrossRef Full Text | Google Scholar

34. Natsuaki S, Goto K, Nakamura K, Yamada M, Ueo H, Komori T, et al. Fatal winter dysentery with severe anemia in an adult cow. J Vet Med Sci (2007) 69(9):957–60. doi: 10.1292/jvms.69.957

PubMed Abstract | CrossRef Full Text | Google Scholar

35. Roberfroid MB. Concepts and strategy of functional food science: the European perspective. Am J Clin Nutr (2000) 71(6 Suppl):1660S–4S; discussion 74S-5S. doi: 10.1093/ajcn/71.6.1660S

PubMed Abstract | CrossRef Full Text | Google Scholar

36. Gapper LW, Copestake DE, Otter DE, Indyk HE. Analysis of bovine immunoglobulin G in milk, colostrum and dietary supplements: a review. Anal Bioanal Chem (2007) 389(1):93–109. doi: 10.1007/s00216-007-1391-z

PubMed Abstract | CrossRef Full Text | Google Scholar

37. Tacket CO, Binion SB, Bostwick E, Losonsky G, Roy MJ, Edelman R. Efficacy of bovine milk immunoglobulin concentrate in preventing illness after Shigella flexneri challenge. Am J Trop Med Hyg (1992) 47(3):276–83. doi: 10.4269/ajtmh.1992.47.276

PubMed Abstract | CrossRef Full Text | Google Scholar

38. Korhonen H, Marnila P, Gill HS. Bovine milk antibodies for health. Br J Nutr (2000) 84 Suppl 1:S135–46. doi: 10.1017/S0007114500002361

PubMed Abstract | CrossRef Full Text | Google Scholar

39. Yolken RH, Losonsky GA, Vonderfecht S, Leister F, Wee SB. Antibody to human rotavirus in cow’s milk. N Engl J Med (1985) 312(10):605–10. doi: 10.1056/NEJM198503073121002

PubMed Abstract | CrossRef Full Text | Google Scholar

40. Takahashi N, Eisenhuth G, Lee I, Laible N, Binion S, Schachtele C. Immunoglobulins in milk from cows immunized with oral strains of Actinomyces, Prevotella, Porphyromonas, and Fusobacterium. J Dent Res (1992) 71(8):1509–15. doi: 10.1177/00220345920710080901

PubMed Abstract | CrossRef Full Text | Google Scholar

41. Loimaranta V, Tenovuo J, Korhonen H. Combined inhibitory effect of bovine immune whey and peroxidase-generated hypothiocyanite against glucose uptake by Streptococcus mutans. Oral Microbiol Immunol (1998) 13(6):378–81. doi: 10.1111/j.1399-302X.1998.tb00695.x

PubMed Abstract | CrossRef Full Text | Google Scholar

42. Ulfman LH, Leusen JHW, Savelkoul HFJ, Warner JO, van Neerven RJJ. Effects of Bovine Immunoglobulins on Immune Function, Allergy, and Infection. Front Nutr (2018) 5:52. doi: 10.3389/fnut.2018.00052

PubMed Abstract | CrossRef Full Text | Google Scholar

43. Jasion VS, Burnett BP. Survival and digestibility of orally-administered immunoglobulin preparations containing IgG through the gastrointestinal tract in humans. Nutr J (2015) 14:22. doi: 10.1186/s12937-015-0010-7

PubMed Abstract | CrossRef Full Text | Google Scholar

44. Pérez-Bosque A, Miró L, Polo J, Russell L, Campbell J, Weaver E, et al. Dietary plasma protein supplements prevent the release of mucosal proinflammatory mediators in intestinal inflammation in rats. J Nutr (2010) 140(1):25–30. doi: 10.3945/jn.109.112466

PubMed Abstract | CrossRef Full Text | Google Scholar

45. Wu YG, Tang C, Hong L, Zhou Z, Dong J, Yin X, et al. Prolonged presence of SARS-CoV-2 viral RNA in faecal samples. Lancet Gastroenterol Hepatol (2020) 5:434–5. doi: 10.1016/S2468-1253(20)30083-2

PubMed Abstract | CrossRef Full Text | Google Scholar

46. Xu Y, Li X, Zhu B, Liang H, Fang C, Gong Y, et al. Characteristics of pediatric SARS-CoV-2 infection and potential evidence for persistent fecal viral shedding. Nat Med (2020) 26(4):502–5. doi: 10.1038/s41591-020-0817-4

PubMed Abstract | CrossRef Full Text | Google Scholar

47. Jackwood MW, de Wit S. Infectious Bronchitis. In: Swayne DE, editor. Diseases of Poultry. Hoboken, NJ, USA: John Wiley & Sons, Inc (2020). p. 167–88.

Google Scholar

48. Tizard IR. Vaccination against coronaviruses in domestic animals. Vaccine (2020) 38(33):5123–30. doi: 10.1016/j.vaccine.2020.06.026

PubMed Abstract | CrossRef Full Text | Google Scholar

49. Homberger FR. Maternally-derived passive immunity to enterotropic mouse hepatitis virus. Arch Virol (1992) 122(1-2):133–41. doi: 10.1007/BF01321123

PubMed Abstract | CrossRef Full Text | Google Scholar

50. Fox A, Marino J, Amanat F, Krammer F, Hahn-Holbrook J, Zolla-Pazner S, et al. Evidence of a significant secretory-IgA-dominant SARS-CoV-2 immune response in human milk following recovery from COVID-19. medRxiv (2020) 2020.05.04.20089995. doi: 10.1101/2020.05.04.20089995

CrossRef Full Text | Google Scholar

51. Loos C, Atyeo C, Fischinger S, Burke J, Slein MD, Streeck H, et al. Evolution of Early SARS-CoV-2 and Cross-Coronavirus Immunity. mSphere (2020) 5(5):e00622–20. doi: 10.1128/mSphere.00622-20

PubMed Abstract | CrossRef Full Text | Google Scholar

52. Ben Mkaddem S, Benhamou M, Monteiro RC. Understanding Fc Receptor Involvement in Inflammatory Diseases: From Mechanisms to New Therapeutic Tools. Front Immunol (2019) 10:811. doi: 10.3389/fimmu.2019.00811

PubMed Abstract | CrossRef Full Text | Google Scholar

53. Crouch CF, Bielefeldt Ohmann H, Watts TC, Babiuk LA. Chronic shedding of bovine enteric coronavirus antigen-antibody complexes by clinically normal cows. J Gen Virol (1985) 66( Pt 7):1489–500. doi: 10.1099/0022-1317-66-7-1489

PubMed Abstract | CrossRef Full Text | Google Scholar

54. Silva-Sanchez A, Randall TD. Anatomical Uniqueness of the Mucosal Immune System (GALT, NALT, iBALT) for the Induction and Regulation of Mucosal Immunity and Tolerance. In: Mucosal Vaccines. Elsevier (2020). p. 21–54. doi: 10.1016/B978-0-12-811924-2.00002-X

CrossRef Full Text | Google Scholar

55. Rodriguez-Argente F, Alba-Dominguez M, Ortiz-Muñoz E, Ortega-Gonzalez A Oromucosal immunomodulation as clinical spectrum mitigating factor in SARS‐CoV‐2 infection. Scand J Immunol (2020) 00:e12972. doi: 10.1111/sji.12972

CrossRef Full Text | Google Scholar

56. Janeway CA Jr, Travers P, Walport M, Shlomchik MJ. The complement system and innate immunity. In: Immunobiology: The Immune System in Health and Disease. 5th edition. New York: Garland Science (2001).

Google Scholar

57. Spiegel M, Pichlmair A, Mühlberger E, Haller O, Weber F. The antiviral effect of interferon-beta against SARS-coronavirus is not mediated by MxA protein. J Clin Virol (2004) 30(3):211–3. doi: 10.1016/j.jcv.2003.11.013

PubMed Abstract | CrossRef Full Text | Google Scholar

58. Agematsu K. Memory B cells and CD27. Histol Histopathol (2000) 15(2):573–6. doi: 10.14670/HH-15.573

PubMed Abstract | CrossRef Full Text | Google Scholar

59. Nielsen SCA, Yang F, Jackson KJL, Hoh RA, Röltgen K, Stevens B, et al. Human B cell clonal expansion and convergent antibody responses to SARS-CoV-2. Cell Host Microbe (2020) 28(4):516–25.e5. doi: 10.21203/rs.3.rs-27220/v1

PubMed Abstract | CrossRef Full Text | Google Scholar

Keywords: BCoV, SARS-CoV-2, immune milk, COVID-19, control

Citation: Arenas A, Borge C, Carbonero A, Garcia-Bocanegra I, Cano-Terriza D, Caballero J and Arenas-Montes A (2021) Bovine Coronavirus Immune Milk Against COVID-19. Front. Immunol. 12:637152. doi: 10.3389/fimmu.2021.637152

Received: 02 December 2020; Accepted: 03 March 2021;
Published: 23 March 2021.

Edited by:

Alexandros Tsoupras, University of Limerick, Ireland

Reviewed by:

François J. M. A. Meurens, UMR INRAE-Oniris 1300 Oniris-Nantes Atlantic National College of Veterinary Medicine, France
Markus Xie, Genentech, United States

Copyright © 2021 Arenas, Borge, Carbonero, Garcia-Bocanegra, Cano-Terriza, Caballero and Arenas-Montes. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Antonio Arenas, arenas@uco.es

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