Geoffrey Lynn - Academia.edu (original) (raw)

Papers by Geoffrey Lynn

Vaccine, Dec 1, 2020

Tick-borne diseases pose a global medical problem. As transmission of tick-borne pathogens to the... more Tick-borne diseases pose a global medical problem. As transmission of tick-borne pathogens to their hosts occurs during tick feeding, development of vaccines thwarting this process could potentially prevent transmission of multiple tick-borne pathogens. The idea of tick vaccines is based on the phenomenon of acquired tick immunity, rejection of ticks feeding on hosts which were repeatedly infested by ticks. Recently, we demonstrated that saliva of the blacklegged tick Ixodes scapularis, which is the main vector of tick-borne pathogens in northeast USA, is sufficient for induction of tick immunity in the guinea pig model and that immunity directed against tick glycoproteins is important in this phenomenon. Nevertheless, immunity elicited against individual tick salivary antigens, which have been identified and tested so far, provided only modest tick rejection. We therefore now tested fractions of tick saliva produced by liquid chromatography for their ability to induce tick immunity in the guinea pig model. Immunization with all individual fractions elicited antibodies that reacted with tick saliva, however only some fractions displayed the ability to induce robust protective tick immunity. Mass spectrometry analysis led to identification of 24 proteins present only in saliva fractions which were able to induce tick immunity, suggesting suitable candidates for development of a tick vaccine.

CABI eBooks, 2021

This chapter focuses on how climate change, together with land use and anthropogenic disturbances... more This chapter focuses on how climate change, together with land use and anthropogenic disturbances, can impact the biology and ecology of medically important ticks as well as the prevalence of tick-borne diseases in North America.

MBio, Oct 26, 2022

Relapsing fever, caused by diverse Borrelia spirochetes, is prevalent in many parts of the world ... more Relapsing fever, caused by diverse Borrelia spirochetes, is prevalent in many parts of the world and causes significant morbidity and mortality. To investigate the pathoetiology of relapsing fever, we performed a high-throughput screen of Borrelia-binding host factors using a library of human extracellular and secretory proteins and identified CD55 as a novel host binding partner of Borrelia crocidurae and Borrelia persica, two agents of relapsing fever in Africa and Eurasia. CD55 is present on the surface of erythrocytes, carries the Cromer blood group antigens, and protects cells from complement-mediated lysis. Using flow cytometry, we confirmed that both human and murine CD55 bound to B. crocidurae and B. persica. Given the expression of CD55 on erythrocytes, we investigated the role of CD55 in pathological B. crocidurae-induced erythrocyte aggregation (rosettes), which enables spirochete immune evasion. We showed that rosette formation was partially dependent on host cell CD55 expression. Pharmacologically, soluble recombinant CD55 inhibited erythrocyte rosette formation. Finally, CD55-deficient mice infected with B. crocidurae had a lower pathogen load and elevated proinflammatory cytokine and complement factor C5a levels. In summary, our results indicate that CD55 is a host factor that is manipulated by the causative agents of relapsing fever for immune evasion. IMPORTANCE Borrelia species are causative agents of Lyme disease and relapsing fever infections in humans. B. crocidurae causes one of the most prevalent relapsing fever infections in parts of West Africa. In the endemic regions, B. crocidurae is present in ;17% of the ticks and ;11% of the rodents that serve as reservoirs. In Senegal, ;7% of patients with acute febrile illness were found to be infected with B. crocidurae. There is little information on host-pathogen interactions and how B. crocidurae manipulates host immunity. In this study, we used a high-throughput screen to identify host proteins that interact with relapsing fever-causing Borrelia species. We identified CD55 as one of the host proteins that bind to B. crocidurae and B. persica, the two causes of relapsing fever in Africa and Eurasia. We show that the interaction of B. crocidurae with CD55, present on the surface of erythrocytes, is key to immune evasion and successful infection in vivo. Our study further shows the role of CD55 in complement regulation, regulation of inflammatory cytokine levels, and innate immunity during relapsing fever infection. Overall, this study sheds light on host-pathogen interactions during relapsing fever infection in vivo.

Ticks and Tick-borne Diseases, Feb 1, 2019

The hard tick-borne relapsing fever spirochete, Borrelia miyamotoi, has recently gained attention... more The hard tick-borne relapsing fever spirochete, Borrelia miyamotoi, has recently gained attention as a cause of human illness, but fundamental aspects of its enzootic maintenance are still poorly understood. Challenges to experimental studies with B. miyamotoi-infected vector ticks include low prevalence of infection in field-collected ticks and seemingly inefficient horizontal transmission from infected immunocompetent rodents to feeding ticks. To reliably produce large numbers of B. miyamotoi-infected ticks in support of experimental studies, we developed an animal model where immunocompromised Mus musculus SCID mice were used as a source of B. miyamotoi-infection for larval and nymphal Ixodes scapularis ticks. Following needle inoculation with 1 × 10 5 spirochetes, the SCID mice developed a high spirochetemia (greater than 1 × 10 7 copies of B. miyamotoi purB per mL of blood) that persisted for at least 30 d after inoculation. In comparison, immunocompetent M. musculus CD-1 mice developed transient infections, detectable for only 2-8 d within the first 16 d after needle inoculation, with a brief, lower peak spirochetemia (8.5 × 10 4-5.6 × 10 5 purB copies per mL of blood). All larval or nymphal ticks fed on infected SCID mice acquired B. miyamotoi, but frequent loss of infection during the molt led to the proportion infected ticks of the resulting nymphal or adult stages declining to 22-29%. The ticks that remained infected after the molt had well-disseminated infections which then persisted through successive life stages, including transmission to larval offspring.

University of Minnesota Ph.D. dissertation. September 2016. Major: Entomology. Advisor: Ulrike Mu... more University of Minnesota Ph.D. dissertation. September 2016. Major: Entomology. Advisor: Ulrike Munderloh. 1 computer file (PDF); xiii, 110 pages.

Ticks and Tick-borne Diseases, May 1, 2020

Ticks and tick-borne diseases are on the rise world-wide and vaccines to prevent transmission of ... more Ticks and tick-borne diseases are on the rise world-wide and vaccines to prevent transmission of tick-borne diseases is an urgent public health need. Tick transmission of pathogens to the mammalian host occurs during tick feeding. Therefore, it is reasoned that vaccine targeting of tick proteins essential for feeding would thwart tick feeding and consequently prevent pathogen transmission. The phenomenon of acquired tick-immunity, wherein, repeated tick infestations of non-natural hosts results in the development of host immune responses detrimental to the tick feeding has served as a robust paradigm in the pursuit of tick salivary antigens that may be vaccine targeted. While several salivary antigens have been identified, immunity elicited against these antigens have only provided modest tick rejection. This has raised the possibility that acquired tick-immunity is directed against tick components other than tick salivary antigens. Using Ixodes scapularis, the blacklegged tick, that vectors several human pathogens, we demonstrate that immunity directed against tick salivary glycoproteins is indeed sufficient to recapitulate the phenomenon of tick-resistance. These observations emphasize the utility of tick salivary glycoproteins as viable vaccine targets to thwart tick feeding and direct our search for anti-tick vaccine candidates.

Nature Reviews Microbiology, Jul 10, 2020

Lyme disease is a tick-borne disease caused by the spirochaete Borrelia burgdorferi, which is tra... more Lyme disease is a tick-borne disease caused by the spirochaete Borrelia burgdorferi, which is transmitted enzootically between ticks and their hosts, resulting in approximately 300,000 cases annually in the United States 1,2. Globally, several species within the B. burgdorferi sensu lato complex have been identified as human pathogens, however, in the United States, nearly all Lyme disease is caused by B. burgdorferi sensu stricto (referred to as B. burgdorferi in this Review). Erythema migrans, the characteristic expanding rash, is an indicator of early acute infection, although the disease can also present with a variety of non-specific clinical signs. Spirochaetes enter the human skin at the tick bite site and then use internal periplasmic flagella to migrate to distal tissues, including the heart and joints 3. Untreated infections can progress to multisystemic manifestations including rheumatologic, neurologic and cardiac disease. Similar versions of Lyme disease occur throughout the Northern Hemisphere, where Ixodes tick species are present. In Europe, Lyme borreliosis is caused by B. burgdorferi sensu lato complex spirochaetes (Box 1), which may infect as many as 85,000 persons annually, while in Asia fewer epidemiological studies have been reported, and it is likely that the true incidence is not well understood. The genome of B. burgdorferi consists of an approximately 1-Mb linear chromosome and at least 17 circular and linear plasmids, many of which are highly stable and contain genes that are crucial for survival 4,5 (Box 2). Gene expression is highly regulated to enable the spirochaete to adapt to the different environments as it cycles between an arthropod host and a vertebrate host 6. External cues from the host, such as temperature, pH, CO 2 levels and other biotic factors, as well as host species are important factors that regulate gene expression in B. burgdorferi 7-10. B. burgdorferi undergoes several changes during transmission from the tick to the host to adapt to the new conditions. At the bite site, the spirochaete must evade the immune defences of the mammalian host to extravasate and establish infection in other tissues. Although B. burgdorferi genome encodes several proteins to facilitate these functions, it also relies heavily on interactions with tick salivary proteins injected into the bite site during the initial stage of vertebrate infection. Understanding how the spirochaetes and the tick host interact is crucial to better understand infection, pathogen transmission and potential targeted therapies. In the United States, most tick-borne infections are transmitted by the bite of the blacklegged tick, Ixodes scapularis, including infections with B. burgdorferi, Borrelia miyamotoi, Borrelia mayonii, Babesia microti, Ehrlichia muris eauclairensis, Anaplasma phagocytophilum and Powassan virus. This three-host tick species is the primary vector for Lyme disease-causing B. burgdorferi spirochaetes. The life cycle of I. scapularis spans 2-4 years and includes egg, larval, nymphal and adult stages.

American Journal of Tropical Medicine and Hygiene, Jan 6, 2021

In many regions where ticks negatively impact public health or economic production, multiple medi... more In many regions where ticks negatively impact public health or economic production, multiple medically important tick species may have overlapping geographic distribution, and in North America, this includes members of Ixodes, Dermacentor, and Amblyomma genera. Acquired tick resistance is the process by which some animals develop an immune response against feeding ticks after one or more exposures. This form of immunity can restrict the ability of ticks to feed and may inhibit transmission of pathogens. Likewise, many proteins present in tick saliva are conserved among tick species, and prior studies have reported cross-protective host immunity against certain combinations of ticks. In this study, we used a guinea pig model to assess whether host resistance against Ixodes scapularis could confer protection against two other medically important tick vectors, Dermacentor variabilis and Amblyomma americanum. Tick challenges using nymphs were used to induce host resistance against a primary species, followed by additional challenge using a secondary tick species. Tick attachment to hosts and engorgement weights were reduced significantly for D. variabilis and A. americanum feeding on I. scapularis-sensitized hosts. Reciprocally, I. scapularis engorgement weights were reduced to a lesser extent, and attachment was unaffected when feeding on hosts sensitized with either D. variabilis or A. americanum. These results indicate that immunity against I. scapularis could potentially be exploited for use in an antitick vaccine targeting multiple tick species and their associated pathogens.

Ticks and Tick-borne Diseases, Sep 1, 2022

Parasites & Vectors, Jan 28, 2017

Background: The Ehrlichia muris-like agent (EMLA) is a newly recognized human pathogen in the Nor... more Background: The Ehrlichia muris-like agent (EMLA) is a newly recognized human pathogen in the North Central United States. Although blacklegged ticks (Ixodes scapularis) have been identified as capable vectors, wild reservoirs have not yet been established for EMLA. As key hosts for I. scapularis, white-footed mice (Peromyscus leucopus) are important reservoirs for various tick-borne pathogens, and potentially, for EMLA. The objective of this study was to evaluate reservoir competence in P. leucopus using a natural vector. Results: Mice acquired EMLA infection from feeding ticks and were able to transmit infection to naïve ticks. Transmission between simultaneously feeding tick life stages was also demonstrated. Infections in mice were acute and severe, with systemic dissemination. Limited host survival and clearance of infection among survivors resulted in a narrow interval where EMLA could be acquired by feeding ticks. Conclusions: Peromyscus leucopus is a competent reservoir of EMLA and likely to play a role in its enzootic transmission cycle. The duration and severity of EMLA infection in these hosts suggests that tick phenology is a critical factor determining the geographic distribution of EMLA in North America.

mBio

Borrelia species are causative agents of Lyme disease and relapsing fever infections in humans. B... more Borrelia species are causative agents of Lyme disease and relapsing fever infections in humans. B. crocidurae causes one of the most prevalent relapsing fever infections in parts of West Africa. In the endemic regions, B. crocidurae is present in ~17% of the ticks and ~11% of the rodents that serve as reservoirs.

Ticks and Tick-borne Diseases

Experimental and Applied Acarology

The cattle fever tick, Rhipicephalus (Boophilus) microplus, is the most economically important ti... more The cattle fever tick, Rhipicephalus (Boophilus) microplus, is the most economically important tick worldwide. Infestations with this tick can lead to direct damage and cattle mortality due to the transmission of potentially deadly pathogens. Management of this tick species has been focused on the use of synthetical acaricides; however, the emergence of acaricide resistance to single or multiple active ingredients has resulted in a need for novel acaricide compounds. Among potential avenues for the discovery of novel acaricides are plant-derived compounds. The efficacy of five organic compounds (nootkatone, Stop the Bites®, BioUD®, lavender oil, and cedarwood oil) was evaluated using larval immersion tests (LITs), repellency assays, and adult immersion tests (AITs). The results from the LITs indicate that three of the organic compounds (NootkaShield™, Stop the Bites, BioUD) led to significant mortalities at low concentrations (0.2, 0.02, and 0.08%, respectively). By comparison, lave...

The American Journal of Tropical Medicine and Hygiene

ABSTRACTIn many regions where ticks negatively impact public health or economic production, multi... more ABSTRACTIn many regions where ticks negatively impact public health or economic production, multiple medically important tick species may have overlapping geographic distribution, and in North America, this includes members of Ixodes, Dermacentor, and Amblyomma genera. Acquired tick resistance is the process by which some animals develop an immune response against feeding ticks after one or more exposures. This form of immunity can restrict the ability of ticks to feed and may inhibit transmission of pathogens. Likewise, many proteins present in tick saliva are conserved among tick species, and prior studies have reported cross-protective host immunity against certain combinations of ticks. In this study, we used a guinea pig model to assess whether host resistance against Ixodes scapularis could confer protection against two other medically important tick vectors, Dermacentor variabilis and Amblyomma americanum. Tick challenges using nymphs were used to induce host resistance again...

Vaccine, 2021

Guinea pigs exposed to multiple infestations with Ixodes scapularis ticks develop acquired resist... more Guinea pigs exposed to multiple infestations with Ixodes scapularis ticks develop acquired resistance to ticks, which is also known as tick immunity. The I. scapularis salivary components that contribute to tick immunity are likely multifactorial. An anticoagulant that inhibits factor Xa, named Salp14, is present in tick saliva and is associated with partial tick immunity. A tick bite naturally releases tick saliva proteins into the vertebrate host for several days, which suggests that the mode of antigen delivery may influence the genesis of tick immunity. We therefore utilized Salp14 as a model antigen to examine tick immunity using mRNA lipid nanoparticles (LNPs), plasmid DNA, or recombinant protein platforms. salp14 containing mRNA-LNPs vaccination elicited erythema at the tick bite site after tick challenge that occurred earlier, and that was more pronounced, compared with DNA or protein immunizations. Humoral and cellular responses associated with tick immunity were directed towards a 25 amino acid region of Salp14 at the carboxy terminus of the protein, as determined by antibody responses and skin-testing assays. This study demonstrates that the model of antigen delivery, also known as the vaccine platform, can influence the genesis of tick immunity in guinea pigs. mRNA-LNPs may be useful in helping to elicit erythema at the tick bite site, one of the most important early hallmarks of acquired tick resistance. mRNA-LNPs containing tick genes is a useful platform for the development of vaccines that can potentially prevent selected tick-borne diseases.

Parasites & vectors, Jan 28, 2017

The Ehrlichia muris-like agent (EMLA) is a newly recognized human pathogen in the North Central U... more The Ehrlichia muris-like agent (EMLA) is a newly recognized human pathogen in the North Central United States. Although blacklegged ticks (Ixodes scapularis) have been identified as capable vectors, wild reservoirs have not yet been established for EMLA. As key hosts for I. scapularis, white-footed mice (Peromyscus leucopus) are important reservoirs for various tick-borne pathogens, and potentially, for EMLA. The objective of this study was to evaluate reservoir competence in P. leucopus using a natural vector. Mice acquired EMLA infection from feeding ticks and were able to transmit infection to naïve ticks. Transmission between simultaneously feeding tick life stages was also demonstrated. Infections in mice were acute and severe, with systemic dissemination. Limited host survival and clearance of infection among survivors resulted in a narrow interval where EMLA could be acquired by feeding ticks. Peromyscus leucopus is a competent reservoir of EMLA and likely to play a role in i...

Human pathogens transmitted by ticks undergo complex life cycles alternating between the arthropo... more Human pathogens transmitted by ticks undergo complex life cycles alternating between the arthropod vector and a mammalian host. While the latter has been investigated to a greater extent, examination of the biological interactions between microbes and the ticks that carry them presents an equally important opportunity for disruption of the disease cycle. In this study, we used in situ hybridization to demonstrate infection by the Ehrlichia muris-like or-ganism, a newly recognized human pathogen, of Ixodes scapularis ticks, a primary vector for several important human disease agents. This allowed us to assess whole sectioned ticks for the patterns of tissue invasion, and demonstrate generalized dissemination of ehrli-chiae in a variety of cell types and organs within ticks infected naturally via blood feeding. Electron microscopy was used to confirm these results. Here we describe a strong ehrlichial affinity for epithelial cells, neuronal cells of the synganglion, salivary glands, a...

Climate, ticks and disease, 2021

Science Translational Medicine, 2021

An Ixodes scapularis saliva mRNA vaccine induces tick resistance and prevents Borrelia burgdorfer... more An Ixodes scapularis saliva mRNA vaccine induces tick resistance and prevents Borrelia burgdorferi infection in guinea pigs.