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The COVID-19 pandemic is a serious global health threat caused by severe acute respiratory syndrome of coronavirus 2 (SARS-CoV-2). Symptoms of COVID-19 are highly variable with common hyperactivity of immune responses known as a "cytokine storm". In fact, this massive release of inflammatory cytokines into in the pulmonary alveolar structure is a main cause of mortality during COVID-19 infection. Current management of COVID-19 is supportive and there is no common clinical protocol applied to suppress this pathological state. Lactoferrin (LF), an iron binding protein, is a first line defense protein that is present in neutrophils and excretory fluids of all mammals, and is well recognized for its role in maturation and regulation of immune system function. Also, due to its ability to sequester free iron, LF is known to protect against insult-induced oxidative stress and subsequent "cytokine storm" that results in dramatic necrosis within the affected tissue. Review of the literature strongly suggests utility of LF to silence the "cytokine storm", giving credence to both prophylactic and therapeutic approaches towards combating COVID-19 infection., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Methicillin-resistant Staphylococcus aureus (MRSA) infection remains a serious hazard to global health. The use of immune modulatory therapy to combat infection is gaining an interest as a novel treatment alternative. Lactoferrin (LF), an iron binding protein with immune modulating properties, has the potential to modify the course of systemic MRSA infection. Specifically, LF is capable of limiting deleterious inflammatory responses while promoting the development of antigen specific T-cell activity. The efficacy of a novel recombinant mouse LF (rmLF) to protect against MRSA infection was examined in a mouse peritonitis model. BALB/c mice were infected with a lethal dose of MRSA and treated at 2h post-infection with rmLF. Effects of rmLF on MRSA-infected primary monocytes and granulocytes were analyzed for inflammatory mediators. The rmLF treated mice demonstrated a modest increase in survival of more than 24h, albeit with reduced bacteremia. Serum cytokines, IL-17 and IL-6, were significantly reduced post-challenge post-rmLF treatment. The rmLF led to a minor decrease in IL-1b, and a slight increase in TNF-a production. Preliminary investigation towards human clinical relevance was accomplished using human blood derived monocytes and granulocytes infected with MRSA and treated with homologous recombinant human LF (rhLF). Treatment with (rhLF) led to increased production of IFN-g and IL-2. The human cell studies also showed a concurrent decrease in TNF-a, IL-6, IL-1b, IL-12p40, and IL-10. These results indicate that the rmLF and rhLF have a high degree of overlap to modify inflammatory responses, although differences in activities were observed between the two heterologous recombinant molecules., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Hypotension is a physiologic state of low blood pressure, the causes of which range from dehydration to underlying serious medical disorders. The aim of this study was to assess the utility of lactoferrin (LF), a natural immunomodulator, to restrain LPS-induced hypotension in rats. LF has previously demonstrated a role in mediation of immune responses, including control of inflammatory cytokine production during acute inflammation. Rats were administered with LF by gavage at 1h or 18 h prior to LPS injections. Heart rate (HR) and mean arterial blood pressure (MAP) were continuously recorded post LPS administration for 6 h. Simultaneously to hemodynamic measurements, serum was examined for TNF-α, IL-6, and TGF-β production. At termination, the proximal duodenum was subjected to histopathological analysis. LF administered at 1h prior to LPS protected rats from the LPS-induced hypotension. The protective effect on MAP was also apparent when LF was administered as a pretreatment 18 h prior to LPS challenge, although the effect was lessened. For all groups, LF pretreatment led to a minor, but insignificant, improvement in HR post LPS administration. In addition, when rats were given LF 1 h before LPS, they showed a significant decrease in serum TNF-α and IL-6 production. LF did not affect the production level of serum TGF-β. Of high importance, LF was able to confer histo-pathological protection of intestinal tissue post LPS administration, for both the 1h and 18 h LF pretreatment groups. These studies indicate a potential for clinical utility of LF to control hypotension., (Published by Elsevier B.V.)

Colostrinin (CLN) is a uniform mixture of low-molecular weight proline-rich polypeptides isolated from the mother's first milk, colostrum. Exposure of cells to CLN decreases intracellular levels of reactive oxygen species by regulating glutathione metabolism and modulating activities of antioxidant enzymes and mitochondrial function. It also inhibits beta amyloid-induced apoptosis and induces neurite outgrowth of pheochromocytoma cells. Administration of CLN to Alzheimer's disease patients has resulted in a stabilizing effect on cognitive function. We analyzed CLN-induced gene expression changes using high-density oligonucleotide arrays and transcriptomal network analysis. We found that CLN elicited highly complex and multiphasic changes in the gene expression profile of treated cells. CLN treatment affected a total of 58 molecular networks, 27 of which contained at least 10 differentially expressed genes. Here we present CLN-modulated gene networks as potential underlying molecular mechanisms leading to the reported effects of CLN on cellular oxidative state, chemokine and cytokine production, and cell differentiation, as well as on pathological processes like allergy, asthma, Alzheimer's, and other neurological diseases. Based on our results, we also predict possible modulatory effects of CLN on adipocytokine gene networks that play a crucial role in the pathobiology of diabetes, cardiovascular disorders, obesity, and inflammation. Taken together, CLN-altered gene expression networks presented here provide the molecular basis for previously described biological phenomena and predict potential fields of application for CLN in the prevention and treatment of diseases.

The ability to control intracellular Mycobacterium tuberculosis (MTB) infection relies on cellular immunity and generation of a strong T-cell helper 1 (T(H)1) response. Lactoferrin, an iron-binding protein with immune regulatory functions, was investigated as an adjuvant to boost Mycobacterium bovis Bacillus Calmette-Guerin (BCG) efficacy. Lactoferrin was initially shown to augment IL-12(p40) production from macrophages stimulated with LPS. A single immunization of mice with Lactoferrin as an adjunct adjuvant resulted in amplified splenocyte proliferative response to heat-killed BCG, and elevated IL-12(p40) production with increased relative ratios of IL-12/IL-10. Furthermore, splenocyte recall response to HK-BCG was augmented for proinflammatory mediators, TNF-alpha, IL-1beta, and IL-6, approaching responses generated to complete Freund's adjuvant (CFA) immunized controls. Specific responses were identified, with significant elevation of IFN-gamma generated during antigenic recall. Subsequent aerosol challenge of Lactoferrin adjuvant immunized mice with virulent M. tuberculosis revealed decreased mycobacterial loads in the lung, and limitation of organism dissemination to a peripheral organ (spleen). These studies indicate that Lactoferrin can act as an adjunct adjuvant to augment cellular immunity and boost BCG efficacy for protection against subsequent challenge with virulent MTB.

Previous studies on cyclophosphamide (CP)-immunocompromised mice showed accelerated reconstitution of immune system function following oral treatment with lactoferrin (LF). The aim of this investigation was to evaluate the ability of mice, treated with a sublethal dose of CP and given LF, to combat bacterial infections. Mice were injected with a single, intraperitoneal dose of CP (350 mg/kg body weight). One group of CP-treated mice was also given LF in drinking water (0.5% solution) for 14 days. Untreated and LF-treated mice served as controls. On day 15 following CP administration, mice were infected intravenously with 10(8) Escherichia coli or 5 x 10(7) Staphylococcus aureus. Twenty-four hours later, the number of colony-forming units (CFU) in spleens and livers were determined. Phenotypic analysis of blood leukocytes was determined, as well as the ability of splenic and peritoneal cells to produce IL-6 spontaneously and in the presence of lipopolysaccharide (LPS). Treatment with CP, or with CP and LF, led to profound reduction of E. coli CFU in the liver and the spleen; treatment with LF alone had significant inhibitory effects on organ enumerated CFU. S. aureus CFUs were also significantly reduced in spleens of mice treated with CP or CP/LF and, to a lesser degree, after LF alone. These effects were also significantly reduced in the livers. Analysis of blood cellular phenotype revealed total number of peripheral leukocytes was lower in the CP-treated group (52.6%) but not significantly different from control values in CP/LF and LF-treated groups (90.7% and 104.6%, respectively). Conversely, percentage of blood neutrophils was markedly elevated in CP and CP/LF groups--62% and 42.5% vs. 18.4% in controls. These findings were accompanied by production of IL-6 by splenic and peritoneal cells which was significantly increased in CP- and CP/LF-treated groups. It was concluded that the increased clearance of bacteria in the organs of mice treated with CP and CP/LF may result from a rise in the number of neutrophils infiltrating the organs and contributing to accelerated clearance of bacteria. The study also suggests that the ability of cells from CP- and CP/LF-treated mice to produce significantly more IL-6 may also contribute to increased resistance to infections. Lastly, together with our previous data, this study indicates that LF used to reconstitute the antigen-specific immune response in CP-treated mice does not impair their resistance to infection.

Improved nontoxic adjuvants, especially adjuvants capable of inducing cell-mediated immunity (CMI), are needed for research in immunology and for development of human and veterinary vaccines. Bovine Lactoferrin, an effector molecule shown to directly participate in host defense, was assessed at various concentrations as an adjuvant component for induction of DTH responses to sheep red blood cells (SRBC). Subcutaneous immunization with Lactoferrin enhanced delayed type hypersensitivity (DTH) in CBA mice in a dose-dependent fashion; DTH responses were most significantly increased when sensitization was accomplished using Lactoferrin at 50 microg/dose and 250 microg/dose. Furthermore, Lactoferrin admixed with suboptimal dose of SRBC enhanced DTH responses by over 17-fold. Peritoneal cells collected from mice intraperitoneally injected with a 100 microg/dose of Lactoferrin demonstrated modest, but significant, production of TNF-alpha, IL-12 and MIP-1alpha when cultured in vitro, compared to saline-injected controls. J774A.1 murine macrophages stimulated with Lactoferrin resulted in increased TNF-alpha protein production, and upregulated IL-12 and IL-15 mRNA. Levels of message for chemokines MIP-1alpha and MIP-2 were also increased in a dose-dependent way. Taken together, these results indicate that Lactoferrin as an adjuvant may stimulate macrophages to generate a local environment likely to push immune responses towards development and maintenance of CMI.