Infected Vertebrate Research Articles

Novel Parvoviruses from Wild and Domestic Animals in Brazil Provide New Insights into Parvovirus Distribution and Diversity.

Parvoviruses (family Parvoviridae) are small, single-stranded DNA viruses. Many parvoviral pathogens of medical, veterinary and ecological importance have been identified. In this study, we used high-throughput sequencing (HTS) to investigate the diversity of parvoviruses infecting wild and domestic animals in Brazil. We identified 21 parvovirus sequences (including twelve nearly complete genomes and nine partial genomes) in samples derived from rodents, bats, opossums, birds and cattle in Pernambuco, São Paulo, Paraná and Rio Grande do Sul states. These sequences were investigated using phylogenetic and distance-based approaches and were thereby classified into eight parvovirus species (six of which have not been described previously), representing six distinct genera in the subfamily Parvovirinae. Our findings extend the known biogeographic range of previously characterized parvovirus species and the known host range of three parvovirus genera (Dependovirus, Aveparvovirus and Tetraparvovirus). Moreover, our investigation provides a window into the ecological dynamics of parvovirus infections in vertebrates, revealing that many parvovirus genera contain well-defined sub-lineages that circulate widely throughout the world within particular taxonomic groups of hosts.

Seroprevalence of Toxoplasma gondii in Military Personnel and their Families Referred to the Military Hospital in Tehran, Iran

Background: Toxoplasmosis is one of the world's most common infections in human and other warm-blooded vertebrates and has the most extensive universal spread. The purpose of this study is determining the seroprevalence of human Toxoplasma gondii infection, in the military personnel and their families referred to Baqiyatallah hospital, 2011-2015. M aterials and Methods: In this cross-sectional study, the serum of 3370 person contain 770 men and 2600 women attending the laboratories were selected and after completing the questionnaires and also by implementing Chemiluminescence method, these serums were examined for the presence of IgM and IgG immunoglobulins of the Toxoplasma gondii . R es ults: The results were analyzed using the chi-square test. They showed that there were no statistical relationships between the prevalence of IgG and gender in 2011, 2013, (P>0.05) but there were significant relationships between them in 2012, 2014 and 2015 (P 0.05). The results showed that there were statistical relationships among IgG and age (P 0.05). C onclusion: The results showed high prevalence of Toxoplasmosis in the military personnel and their families in Baqiyatallah hospital. The prevalence of IgG was somehow in the range and positive IgG titer was somewhat higher than what was reported in other studies in the North-West of the country; this could be partly due to the sensitivity and specificity of Chemiluminescence method compared to other methods of serology in diagnosis of Toxoplasmosis.

Porcine serum amyloid A3 is expressed in extrahepatic tissues and facilitates viral replication during porcine respiratory and reproductive syndrome virus infection

Serum amyloid A (SAA) is an acute phase protein that is expressed rapidly in response to infection and inflammation in vertebrates. Here, we detected the expression of porcine SAA3, an isoform of porcine SAA, during porcine respiratory and reproductive syndrome virus (PRRSV) infection, which is a major threat to the pig industry. In response to PRRSV infection, porcine SAA3 expression was upregulated significantly in porcine pulmonary alveolar macrophages and in extrahepatic tissues, including the lungs and inguinal, mandibular, and hilar lymph nodes, which were affected mainly by PRRSV infection, demonstrating that porcine SAA3 is a tissue-derived isoform that is induced in extrahepatic tissues during the acute phase response. Overexpression of porcine SAA3 increased PRRSV titers in cultured cells, and the exogenous administration of porcine SAA3 facilitated PRRSV adsorption to cells, suggesting that porcine SAA3 assists PRRSV replication. Our data provide insights into the role of porcine SAA3 during PRRSV infection.

Differential outcomes of Zika virus infection in Aedes aegypti orally challenged with infectious blood meals and infectious protein meals.

BackgroundInfection of mosquitoes is an essential step for the transmission of mosquito-borne arboviruses in nature. Engorgement of infectious blood meals from viremic infected vertebrate hosts allows the entry of viruses and initiates infection of midgut epithelial cells. Historically, the infection process of arboviruses in mosquitoes has been studied through the engorgement of mosquitoes from viremic laboratory animals or from artificial feeders containing blood mixed with viruses harvested from cell cultures. The latter approach using so-called artificial blood meals is more frequently used since it is readily optimized to maximize viral titer, negates the use of animals and can be used with viruses for which there are no small animal models. Use of artificial blood meals has enabled numerous studies on mosquito infections with a wide variety of viruses; however, as described here, with suitable modification it can also be used to study the interplay between infection, specific blood components, and physiological consequences associated with blood engorgement. For hematophagous female mosquitoes, blood is the primary nutritional source supporting all physiological process including egg development, and also influences neurological processes and behaviors such as host-seeking. Interactions between these blood-driven vector biological processes and arbovirus infection that is mediated via blood engorgement have not yet been specifically studied. This is in part because presentation of virus in whole blood inevitably induces enzymatic digestion processes, hormone driven oogenesis, and other biological changes. In this study, the infection process of Zika virus (ZIKV) in Aedes aegypti was characterized by oral exposure via viral suspension meals within minimally bovine serum albumin complemented medium or within whole blood. The use of bovine serum albumin in infectious meals provides an opportunity to evaluate the role of serum albumin during the process of flavivirus infection in mosquitoes.MethodsInfectious whole blood meals and infectious bovine serum albumin meals containing ZIKV were orally presented to two different groups of Ae. aegypti through membrane feeding. At 7 and 14 days post infection, infectious viruses were detected and viral dissemination from gut to other mosquito tissues was analyzed in orally challenged mosquitoes with 50% tissue culture infectious dose method on Vero76 cells.Results/ConclusionsZika virus infection was significantly impaired among mosquitoes orally challenged with infectious protein meals as compared to infectious whole blood meals. These results indicate the importance of the blood meal in the infection process of arboviruses in mosquitoes. It provides the basis for future studies to identify critical components in the blood of vertebrate hosts that facilitate arbovirus infection in mosquitoes.

A synthetic cationic antimicrobial peptide inhibits inflammatory response and the NLRP3 inflammasome by neutralizing LPS and ATP.

Antimicrobial peptides (AMPs) are one of the most important defense mechanisms against bacterial infections in insects, plants, non-mammalian vertebrates, and mammals. In the present study, a class of synthetic AMPs was evaluated for anti-inflammatory activity. One cationic AMP, GW-A2, demonstrated the ability to inhibit the expression levels of nitric oxide (NO), inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in lipopolysaccharide (LPS)-activated macrophages. GW-A2 reduced LPS-induced increases in the phosphorylation of mitogen-activated protein kinase and protein kinase C-α/δ and the activation of NF-κB. GW-A2 also inhibited NLRP3 inflammasome activation induced by LPS and ATP. Furthermore, in the mice injected with LPS, GW-A2 reduced (1) the concentration of IL-1β, IL-6 and TNF-α in the serum; (2) the concentration of TNF-α in the peritoneal lavage; (3) the expression levels of iNOS, COX-2 and NLRP3 in the liver and lung; (4) the infiltration of polymorphonuclear neutrophils in the liver and lung. The underlying mechanisms for the anti-inflammatory activity of GW-A2 were found to be partially due to LPS and ATP neutralization. These results provide insights into how GW-A2 inhibits inflammation and the NLRP3 inflammasome and provide a foundation for the design of rational therapeutics for inflammation-related diseases.

Functional characterization of an aquaporin from a microsporidium, Nosema bombycis.

Microsporidia are a diverse group of eukaryotic organisms, capable of causing parasitic infections in both vertebrates and invertebrates. During the germination process, there is an increase in the osmotic pressure of microsporidian spores. As part of this study, we cloned a homologous aquaporin gene in Nosema bombycis, and named it Nosema bombycis aquaporin (NbAQP). Sequence analysis revealed that the NbAQP contains an open reading frame with a length of 750 bp and encodes a polypeptide of 249 amino acids. Amino acid sequence homology was greater than 50% that of five aquaporins from other microsporidian species. Indirect immunofluorescence (IFA) and immunogold electron microscopy showed NbAQP to be located predominantly in the spore wall of N. bombycis spores. The results of qRT-PCR analysis revealed that NbAQP expression remained high 0 h after inoculation and decreased sharply to 24 h, increased gradually from 2 days and peaked at 6 days. After expression of NbAQP in Xenopus laevis oocytes, it was observed that NbAQP can promote rapid penetration of water into oocytes. The associated permeation rate was 2–3 times that of the water-injected and uninjected oocytes. Antibody blocking experiments showed that the inhibition rate of spore germination was approximately 28% after antibody blocking. The difference in germination rate between the control group and the NbAQP group was significant (P < 0.05). This study shows for the first time that N. bombycis contains functional water channel proteins and provides a platform suitable for further research into the mechanisms underlying the regulation of NbAQP protein expression. Further study of NbAQP and their inhibitors may have significance for prevention of microsporidiosis.

Low density lipopolyprotein inhibits flavivirus acquisition in Aedes aegypti.

Aedes aegypti is the primary vector of a number of human pathogens including dengue virus (DENV) and Zika virus (ZIKV). Ae.aegypti acquires these viruses during the processing of bloodmeals obtained from an infected vertebrate host. Vertebrate blood contains a number of factors that have the potential to modify virus acquisition in the mosquito. Interestingly, low density lipopolyprotein (LDL) levels are decreased during severe DENV infection. Accordingly, we hypothesized that LDL is a modifiable factor that can influence flavivirus acquisition in the mosquito. We found that LDL is endocytosed by Ae.aegypti cells in a dynamin-dependent manner. LDL is also endocytosed by midgut epithelial cells and accumulates at the luminal midgut epithelium during bloodmeal digestion. Importantly, pretreatment with LDL, but not high density lipopolyprotein (HDL), significantly inhibited both DENV and ZIKV infection in vitro, and LDL inhibited ZIKV infection in vivo. This study identifies human LDL or 'bad cholesterol' as a modifiable factor that can inhibit flavivirus acquisition in Ae.aegypti. Identification of modifiable blood factors and critical cellular interactions that mediate pathogen acquisition may lead to novel strategies to disrupt the transmission cycle of vector-borne diseases.

A Tick Antivirulence Protein Potentiates Antibiotics against Staphylococcus aureus.

New strategies are needed to combat antibiotic resistance, especially against pathogens such as methicillin-resistant Staphylococcus aureus A tick antifreeze glycoprotein, IAFGP, possesses potent antibiofilm properties against a variety of clinical pathogens, including S. aureus Synergy between IAFGP, or a peptide (P1) representative of a repeat region of the protein, with different antibiotics was assessed in vitro Antibiotics that synergized with either IAFPG or P1 were further evaluated in vivo using vertebrate and invertebrate infection models. IAFGP readily enhanced the efficacy of antibiotics against S. aureus Synergy with daptomycin, an antibiotic used to treat methicillin-resistant S. aureus, was observed in vitro and in vivo using iafgp-transgenic mice and flies. Furthermore, synergy with ciprofloxacin or gentamicin, antibiotics not generally used to treat S. aureus, was also perceived. The combined effect of the antibiotic and IAFGP was associated with improved permeation of the antibiotic into the cell. Our results highlight that synergy of IAFGP with antibiotics traditionally used to treat this pathogen, and enhancement of the potency of antibiotics not commonly used against this microbe, can provide novel alternative therapeutic strategies to combat bacterial infections.

Genomic innovations linked to infection strategies across emerging pathogenic chytrid fungi

To understand the evolutionary pathways that lead to emerging infections of vertebrates, here we explore the genomic innovations that allow free-living chytrid fungi to adapt to and colonize amphibian hosts. Sequencing and comparing the genomes of two pathogenic species of Batrachochytrium to those of close saprophytic relatives reveals that pathogenicity is associated with remarkable expansions of protease and cell wall gene families, while divergent infection strategies are linked to radiations of lineage-specific gene families. By comparing the host–pathogen response to infection for both pathogens, we illuminate the traits that underpin a strikingly different immune response within a shared host species. Our results show that, despite commonalities that promote infection, specific gene-family radiations contribute to distinct infection strategies. The breadth and evolutionary novelty of candidate virulence factors that we discover underscores the urgent need to halt the advance of pathogenic chytrids and prevent incipient loss of biodiversity.

Malaria Altering Host Attractiveness and Mosquito Feeding

Several studies have suggested that malaria parasites stack the odds of transmission in their favour by manipulating the attraction profiles of their hosts. A recent study provides evidence that a specific parasite factor, (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate, may increase both the attractiveness of infected vertebrates and the susceptibility of mosquitoes to infection.

Mosquito cell-derived West Nile virus replicon particles mimic arbovirus inoculum and have reduced spread in mice

Half of the human population is at risk of infection by an arthropod-borne virus. Many of these arboviruses, such as West Nile, dengue, and Zika viruses, infect humans by way of a bite from an infected mosquito. This infectious inoculum is insect cell-derived giving the virus particles distinct qualities not present in secondary infectious virus particles produced by infected vertebrate host cells. The insect cell-derived particles differ in the glycosylation of virus structural proteins and the lipid content of the envelope, as well as their induction of cytokines. Thus, in order to accurately mimic the inoculum delivered by arthropods, arboviruses should be derived from arthropod cells. Previous studies have packaged replicon genome in mammalian cells to produce replicon particles, which undergo only one round of infection, but no studies exist packaging replicon particles in mosquito cells. Here we optimized the packaging of West Nile virus replicon genome in mosquito cells and produced replicon particles at high concentration, allowing us to mimic mosquito cell-derived viral inoculum. These particles were mature with similar genome equivalents-to-infectious units as full-length West Nile virus. We then compared the mosquito cell-derived particles to mammalian cell-derived particles in mice. Both replicon particles infected skin at the inoculation site and the draining lymph node by 3 hours post-inoculation. The mammalian cell-derived replicon particles spread from the site of inoculation to the spleen and contralateral lymph nodes significantly more than the particles derived from mosquito cells. This in vivo difference in spread of West Nile replicons in the inoculum demonstrates the importance of using arthropod cell-derived particles to model early events in arboviral infection and highlights the value of these novel arthropod cell-derived replicon particles for studying the earliest virus-host interactions for arboviruses.

Regulation of Gene and Protein Expression in the Lyme Disease Spirochete.

The infectious cycle of Borrelia burgdorferi necessitates persistent infection of both vertebrates and ticks, and efficient means of transmission between those two very different types of hosts. The Lyme disease spirochete has evolved mechanisms to sense its location in the infectious cycle, and use that information to control production of the proteins and other factors required for each step. Numerous components of borrelial regulatory pathways have been characterized to date. Their effects are being pieced together, thereby providing glimpses into a complex web of cooperative and antagonistic interactions. In this chapter, we present a broad overview of B. burgdorferi gene and protein regulation during the natural infectious cycle, discussions of culture-based methods for elucidating regulatory mechanisms, and summaries of many of the known regulatory proteins and small molecules. We also highlight areas that are in need of substantially more research.

Molecular cloning and functional characterization of cathepsin B from the sea cucumber Apostichopus japonicus

Cathepsin B (CTSB), a member of lysosomal cysteine protease, is involved in multiple levels of physiological and biological processes, and also plays crucial roles in host immune defense against pathogen infection in vertebrates. However, the function of CTSB within the innate immune system of invertebrates, particularly in marine echinoderms, has been poorly documented. In this study, the immune function of CTSB in Apostichopus japonicus (designated as AjCTSB), a commercially important and disease vulnerable aquaculture specie, was investigated by integrated molecular and protein approaches. A 2153 bp cDNA representing the full-length of AjCTSB was cloned via overlapping ESTs and RACE fragments. AjCTSB contained an open reading frame of 999 bp encoding a secreted protein of 332 amino acid residues with a predicted molecular mass of 36.8 kDa. The deduced amino acid of AjCTSB shared a typical activity center containing three conserved amino acid residues (Cys108, His277 and Asn297). Phylogenetic tree analysis also supported that AjCTSB was a new member of CTSB family with clustering firstly with invertebrate CTSBs. Quantitative real time PCR analysis revealed that AjCTSB was ubiquitously expressed in all examined tissues with the highest levels in intestine. The Vibrio splendidus challenged sea cucumber and LPS-exposed coelomocytes could both significantly boost the expression of AjCTSB. Moreover, the purified recombinant AjCTSB exhibited dose-dependent CTSB activities at the concentration ranged from 0 to 0.24 μg μL−1. Further functional analysis indicated that coelomocytes apoptosis was significantly inhibited by 0.16-fold in vivo and the apoptosis execution Ajcaspase 3 was extremely reduced in Apostichopus japonicus coelomocytes treated with specific AjCTSB siRNA. Collectively, all these results suggested that AjCTSB was an important immune factor and might be served as apoptosis enhancers in pathogen challenged sea cucumber.

Leptospirose – Revisão

Leptospirosis is an infectious systemic disease; its occurrence is evidenced in tropical and subtropical regions. It is prevalent in the Americas, occurring endemically in Latin America and Caribbean. In the Brazil, the disease is endemic; outbreaks are common during the rainy season. Leptospirosis is also considered an occupational risk of disease, affecting agricultural workers (rice paddies and sugarcane), miners, garbage and cleaning charge of public collectors, workers of water and sewage, as well as veterinarians and keepers of animals. In this way, this study proposes a systematic review of the scientific publication on the factors associated with leptospirosis. The method logy screened available studies in SciELO, MEDLINE, and LILACS. The control of animal leptospirosis should be based on the integration of prophylactic measures imposed simultaneously on all three levels of the chain of transmission: infection source (infected vertebrates), transmission routes (water, soil and contaminated fomites), likely vertebrates uninfected and not immunized and protection to it, which is achieved with the use of inactivated vaccines containing the serotypes of Leptospira.

The Role of Cytokine PF4 in the Antiviral Immune Response of Shrimp.

During viral infection in vertebrates, cytokines play important roles in the host defense against the virus. However, the function of cytokines in invertebrates has not been well characterized. In this study, shrimp cytokines involved in viral infection were screened using a cytokine antibody microarray. The results showed that three cytokines, the Fas receptor (Fas), platelet factor 4 (PF4) and interleukin-22 (IL-22), were significantly upregulated in the white spot syndrome virus (WSSV)-challenged shrimp, suggesting that these cytokines played positive regulatory roles in the immune response of shrimp against the virus. Further experiments revealed that PF4 had positive effects on the antiviral immunity of shrimp by enhancing the shrimp phagocytic activity and inhibiting the apoptotic activity of virus-infected hemocytes. Therefore, our study presented a novel mechanism of cytokines in the innate immunity of invertebrates.

Ehrlichioses: An Important One Health Opportunity.

Ehrlichioses are caused by obligately intracellular bacteria that are maintained subclinically in a persistently infected vertebrate host and a tick vector. The most severe life-threatening illnesses, such as human monocytotropic ehrlichiosis and heartwater, occur in incidental hosts. Ehrlichia have a developmental cycle involving an infectious, nonreplicating, dense core cell and a noninfectious, replicating reticulate cell. Ehrlichiae secrete proteins that bind to host cytoplasmic proteins and nuclear chromatin, manipulating the host cell environment to their advantage. Severe disease in immunocompetent hosts is mediated in large part by immunologic and inflammatory mechanisms, including overproduction of tumor necrosis factor α (TNF-α), which is produced by CD8 T lymphocytes, and interleukin-10 (IL-10). Immune components that contribute to control of ehrlichial infection include CD4 and CD8 T cells, natural killer (NK) cells, interferon-γ (IFN-γ), IL-12, and antibodies. Some immune components, such as TNF-α, perforin, and CD8 T cells, play both pathogenic and protective roles. In contrast with the immunocompetent host, which may die with few detectable organisms owing to the overly strong immune response, immunodeficient hosts die with overwhelming infection and large quantities of organisms in the tissues. Vaccine development is challenging because of antigenic diversity of E. ruminantium, the necessity of avoiding an immunopathologic response, and incomplete knowledge of the protective antigens.

C-Myb acts in parallel and cooperatively with Cebp1 to regulate neutrophil maturation in zebrafish

AbstractNeutrophils are the key effectors for generating innate immunity in response to pathogenic infection and tissue injury in vertebrates. Dysregulation of neutrophil development and function is known to associate with various human disorders. Yet, the genetic network that orchestrates lineage commitment, differentiation, and maturation of neutrophils remains incompletely defined. Here, we present an in vivo study to delineate the genetic program underlying neutrophil development during zebrafish embryonic myelopoiesis. We show that loss of c-Myb function has no effect on macrophages but severely impairs neutrophil terminal differentiation, resulting in the accumulation of neutrophils with unsegmented nuclei and scant granule. This neutrophilic defect, which resembles the neutrophil-specific granule deficiency (SGD) caused by the mutations in CCAAT/enhancer-binding protein ε (C/EBPε) in humans, is attributed, at least in part, to the downregulation of the granule protein transcription. Likewise, genetic inactivation of Cebp1, the zebrafish functional homolog of mammalian C/EBPε, also leads to a similar SGD-like phenotype in zebrafish. Genetic epistasis and biochemical analysis further reveals that c-Myb and Cebp1 act in parallel and cooperatively to control neutrophil differentiation by directly regulating granule protein gene transcription. Our study indicates that c-MYB is an intrinsic master regulator for neutrophil terminal differentiation and a potential target in SGD patients.

Alphavirus Infection: Host Cell Shut-Off and Inhibition of Antiviral Responses.

Alphaviruses cause debilitating disease in humans and animals and are transmitted by blood-feeding arthropods, typically mosquitoes. With a traditional focus on two models, Sindbis virus and Semliki Forest virus, alphavirus research has significantly intensified in the last decade partly due to the re-emergence and dramatic expansion of chikungunya virus in Asia, Europe, and the Americas. As a consequence, alphavirus–host interactions are now understood in much more molecular detail, and important novel mechanisms have been elucidated. It has become clear that alphaviruses not only cause a general host shut-off in infected vertebrate cells, but also specifically suppress different host antiviral pathways using their viral nonstructural proteins, nsP2 and nsP3. Here we review the current state of the art of alphavirus host cell shut-off of viral transcription and translation, and describe recent insights in viral subversion of interferon induction and signaling, the unfolded protein response, and stress granule assembly.

Changes in corticosterone concentrations and behavior during Mycoplasma gallisepticum infection in house finches (Haemorhous mexicanus)

Glucocorticoid stress hormones are important for energy mobilization as well as regulation of the immune system, and thus these hormones are particularly likely to both influence and respond to pathogen infection in vertebrates. In this study, we examined how the glucocorticoid stress response in house finches (Haemorhous mexicanus) interacts with experimental infection of the naturally-occurring bacterial pathogen, Mycoplasma gallisepticum (MG). We also investigated whether infection-induced concentrations of corticosterone (CORT), the primary glucocorticoid in birds, were associated with the expression of sickness behavior, the lethargy typically observed in vertebrates early in infection. We found that experimental infection with MG resulted in significantly higher CORT levels on day 5 post-infection, but this effect appeared to be limited to female house finches only. Regardless of sex, infected individuals with greater disease severity had the highest CORT concentrations on day 5 post-infection. House finches exposed to MG exhibited behavioral changes, with infected birds having significantly lower activity levels than sham-inoculated individuals. However, CORT concentrations and the extent of sickness behaviors exhibited among infected birds were not associated. Finally, pre-infection CORT concentrations were associated with reduced inflammation and pathogen load in inoculated males, but not females. Our results suggest that the house finch glucocorticoid stress response may both influence and respond to MG infection in sex-specific ways, but because we had a relatively low sample size of males, future work should confirm these patterns. Finally, manipulative experiments should be performed to test whether the glucocorticoid stress response acts as a brake on the inflammatory response associated with MG infection in house finches.

Overview of Lactoferrin as a Natural Immune Modulator

Lactoferrin is thought to be the most polyvalent protein present in host defense against tissue injuries and infections in vertebrates. Owing to the propensity of its basic N-terminal domain to interact with various microbial and host targets, lactoferrin not only has antimicrobial properties, but also modulates the innate and adaptive immune responses. Lactoferrin may indeed up- and downregulate immune cell activation, migration, and growth. Whereas the immunomodulatory properties of lactoferrin are evidenced from invivo studies using either lactoferrin-knockout, lactoferrin-overexpressing transgenic models, and dietary lactoferrin, few mechanisms from invitro studies have been proposed to explain these properties. The best characterized lactoferrin targets are negatively charged molecules. They encompass pro-inflammatory microbial molecules, such as pathogen-associated molecular patterns (eg, lipopolysaccharide), but also host components such as DNA, the glycosaminoglycan chains of proteoglycans, and surface cell receptors. Signaling through these receptors is thought to be the main lever used by lactoferrin to influence immune cells and cytokine-balance-controlling cell activity. This article aims to review our current understanding, though incomplete, of the many ways lactoferrin influences the complex immune machinery and the known and putative mechanisms that may explain its properties.