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Immunoglobulins and lactoferrrin against viral attacks

August 31, 2020 - 18:33 -- Pierre Lutgen

Pascal Gisenya, Pierre Lutgen

Mucosal surfaces represent a major interface between host and environment. They constitute the point of entry of most infectious pathogens, and are in contact with potentially injurious antigens present in the normal mucosal microflora and in ingested or inhaled substances.

MUCOSAL LININGS ARE RICH IN IMMUNOGLOBULINS

IgA is synthesized in quantities (˜66 mg/kg body weight/day) that exceed by far the combined daily synthesis of all other isotypes. It widely exists in the gastrointestinal tract, respiratory tract, vaginal tract, tears, saliva.
IgA titers are significantly lower in immunodeficient individuals.
Karin Sá Fernandes.Michella Bezerra Lima .Salivary Immunoglobulins in Individuals with Common Variable Immunodeficiency. Brazilian Dental Journal. vol.27 no.6 Nov./Dec. 2016

Other studies seem to indicate that the IgG have a higher antiviral efficiency than IgA and IgM. The IgG isotype cure the disease by neutralizing all progeny virus until all productively infected host cells have died. IgA and IgM isotypes may be ineffective therapeutically because they do not have sufficient access to all tissue sites in which virus is produced during influenza virus pneumonia.
Palladino G, Mozdzanowska K, Washko G, Gerhard W. Virus-neutralizing antibodies of immunoglobulin G (IgG) but not of IgM or IgA isotypes can cure influenza virus pneumonia in SCID mice. J Virol. 1995;69(4):2075-2081

Others have demonstrated that humans produce IgE against respiratory viruses. IgE is part of the antiviral immune response during a respiratory viral infection. IgE was only discovered 50 years ago. IgE is known to provide the biological basis for allergy and immediate hypersensitivity. However, recent data provide some evidence that IgE responses are involved in other inflammatory processes apart from allergy, including several respiratory diseases. IgE binds to mast cells and basophils in the airways.
Kelly BT, Grayson MH. Immunoglobulin E, what is it good for? Ann Allergy Asthma Immunol. 2016;116(3):183-187.
Ota Y, Ikemiyagi Y, Sato T, et al. Measuring local immunoglobulin E in the inferior turbinate nasal mucosa in patients with allergic rhinitis. Allergol Int. 2016;65(4):396-399.
Grayson MH, Cheung D, Rohlfing MM, et al. Induction of high-affinity IgE receptor on lung dendritic cells during viral infection leads to mucous cell metaplasia. J Exp Med. 2007;204(11):2759-2769.

In the skin and mucosal linings IgE may play a crucial barrier against invasion. In the vascular circulation and serum they have a half-life of 2 days, but positive skin tests results were still demonstrated after 50 days. This long-life of the IgE in the skin is a seminal finding.
J. Munyangi, P Gisenya, P Ogwang, P. Lutgen. An unexpected, revolutionary property of Artemisia infusions: immunoglobulins in the skin lead to a long-lasting prophylaxis. PPIJ(-1. 2020.

In a study from Iran it was found that in age groups below 60 versus those above 60 years, IgE titers were around 130 (IU/dl) versus 80. IgA titers in salaiva were more or less constant through the age groups. Gender had no effect on the salivary levels of IgA and IgE.
A Jafarzadeh, M Sadeghi, Salivary IgA and IgE levels in healthy subjects: relation to age and gender. Braz Oral Res 2010, 24, :21-7

In many ways, the oral cavity can act as a focus of infection for the initiation/exaggeration of systemic diseases. Oral bacteria have been shown to be significantly associated with increased risk of systemic diseases.

LACTOFERRIN IN HUMAN SALIVA

Lactoferrin, also known as lactotransferrin, is a protein of the innate immune system. It is an important component present in the saliva that plays an important role in oral diseases. The protein is also present in other exocrine secretions including bronchial mucus, milk, tears, nasal exudates. Lactoferrin is an iron binding glycoprotein (250times higher than for the parent molecule transferrin). Many biological functions have been ascribed to lactoferrin.
The bactericidal and bacteriostatic properties of lactoferrin are well known
Hamosh M. Protective function of proteins and lipids in human milk. Biol Neonate. 1998;74(2):163-76.

Lactoferrin indeed binds strongly to iron, and almost irreversibly. This complex in a dose dependent manner enhances ROS production. A variety of free radical ions inhibits a variety of intracellular parasites and microbes. In parallel there is a 4-fold increase in phagocytic capacity of macrophages and monocytes.
Anand N, Kanwar RK. Effect of lactoferrin protein on red blood cells and macrophages: mechanism of parasite-host interaction. Drug Des Devel Ther. 2015 Jul 27;9:3821-35.
Lima MF, Kierszenbaum F. Lactoferrin effects on phagocytic cell function. I. Increased uptake and killing of an intracellular parasite by murine macrophages and human monocytes. J Immunol. 1985 Jun;134(6):4176-83

Many other anti-microbial and anti-viral functions have since been ascribed to Lactoferrin. In mucosal secretions, lactoferrrin exerts antiviral activity, through its binding to host cells and/or viral particles. It is an important brick in the mucosal wall, effective against both microbial and viral attacks.
Lactoferrin displays antiviral activity against both DNA- and RNA-viruses, including rotavirus, respiratory syncytial virus, herpes viruses and HIV. The antiviral effect lies in the early phase of infection.
B W van der Strate, L Beljaars, Antiviral activities of lactoferrin. Antiviral Res. 2001 Dec;52(3):225-39.
Valenti P, Antonini G. Lactoferrin: an important host defence against microbial and viral attack. Cell Mol Life Sci. 2005;62(22):2576-2587.

A recent review paper shows that lactoferrin has been tested in vitro, in vivo and in human trials against a variety of viruses, with promising results.
Raymond Changa, Tzi Bu Lactoferrin as potential preventative and adjunct treatment for COVID-19. International Journal of Antimicrobial Agents. Volume 56, Issue 3, September 2020, 106118

Bovine lactoferrin has been shown to be effective both at the early stages of viral infection and during its entire course. The most effective seem to be the long storage products like whey.
H Thormar, C Isaacs, Inactivation of enveloped viruses by lipids in stored milk. Antimicrobial Agents and Chemotherapy, 1987, Jan, 27-31
Małaczewska, J., Kaczorek-Łukowska, E., Wójcik, R. et al. Antiviral effects of nisin, lysozyme, lactoferrin and their mixtures against bovine viral diarrhoea virus. BMC Vet Res 15, 318 (2019).
Ng TB, Cheung RC, Wong JH, et al. Antiviral activities of whey proteins. Appl Microbiol Biotechnol. 2015;99(17):6997-7008.

The anti-HIV properties of lactoferrin present in whey have been confirmed in a few case studies in Kivu-RDC (Pascal, Gisenya, personal communication.

Salivary lactoferrin plays an important role in protecting the oral cavity against several oral pathogens. Patient with a immune disorder disease showed 2.5× times higher concentration of lactoferrin compared with healthy subjects.
Skalickova, S; Zitka, O; Krizkova, S; Vlkova, M; Sochor, J; Adam, V; Kizek, R, 2014: Isolation and Determination of Lactoferrin in Human Saliva. CHEMICKE LISTY 108(1), p. 56 - 63

Human sweat also contains lactoferrin, an important element in skin immunity. The recommended frequent washing and disinfection of the hands eventually may have negative effects, the normal protective coating of the skin being affected.
Wu Changxia, Zheng-Fei Liu. Proteomic Profiling of Sweat Exosome Suggests its Involvement in Skin Immunity. Journal of Investigative Dermatology 2017 138(1)
Park JH, Park GT, Cho IH, Sim SM, Yang JM, Lee DY. An antimicrobial protein, lactoferrin exists in the sweat: proteomic analysis of sweat. Exp Dermatol. 2011 Apr;20(4):369-71
Cynthia Ordaz-Pichardo, Nidia León-Sicairos. Lactoferrin: A protein of the innate immune system capable of killing parasitic protozoa. In book: Parasites: Ecology, Diseases and Management: December 2012.
Tang L, Wu JJ, Ma Q, Cui T, Andreopoulos FM, Gil J, Valdes J, Davis SC, Li J. Human lactoferrin stimulates skin keratinocyte function and wound re-epithelialization. Br J Dermatol. 2010 Jul;163(1):38-47

More relevant for the present viral pandemia are the results reported by Serrano et al. that a liposomal bovine Lf supplement containing 32 mg of lactoferrin administered at four to six doses per day for 10 days with zinc 10 mg two to three times daily resulted in 100% recovery of 75 symptomatic SARS-CoV-2-positive patients within 4–5 days, and the same treatment at lower dose appeared to prevent the disease in healthy contacts
Serrano G, Kochergina I, Albors A, Diaz E, Oroval M, Hueso G, et al. Liposomal Lactoferrin as Potential Preventative and Cure for COVID-19. Int J Res Health Sci. 2020;8(1):8-15.

Comments

Submitted by Pierre Lutgen on

Besides immunoglobulins and lactoferrin, there also are numerous defense proteins present in saliva.
T Fabian, P Hermann, Salivary defense proteins. Their network and role in innate and acquired oral immunity. Int J Mol Sci, 2012, 13, 4295-4320
White MR, Helmerhorst EJ, Multiple components contribute to ability of saliva to inhibit influenza viruses. Oral Microbiol Immunol. 2009; 24(1):18-24.

The antibodies present in saliva also catalyze ozone formation, a known antiviral agent. Ozone reacts with blood biomolecules such as unsaturated fatty acids to generate reactive oxygen species, hydrogen peroxide and lipid peroxides. These ozone reaction products will act as ozone messengers stimulating a therapeutic effect instead of a direct attack of the viruses.
Chedly Tizaoui, Ozone : A potential oxidant for Covid-19 virus (SARS-CoV-2). Ozone : Science and Engineering. 18 May 2020.