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Falkeborn, Tina
Publications (10 of 10) Show all publications
Devito, C., Ellegård, R., Falkeborn, T., Svensson, L., Ohlin, M., Larsson, M., . . . Hinkula, J. (2018). Human IgM monoclonal antibodies block HIV-transmission to immune cells in cervico-vaginal tissues and across polarized epithelial cells in vitro. Scientific Reports, 8, Article ID 10180.
Open this publication in new window or tab >>Human IgM monoclonal antibodies block HIV-transmission to immune cells in cervico-vaginal tissues and across polarized epithelial cells in vitro
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2018 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 10180Article in journal (Refereed) Published
Abstract [en]

The importance of natural IgM antibodies in protection against infections is still emerging and these antibodies have a potential role in the maintenance of homeostasis through clearance of apoptotic bodies, complement-dependent mechanisms, inflammation and exclusion of misfolded proteins. Natural IgM act as a first line of defence against unknown hazardous factors and are present in most vertebrates. We investigated the functional capacity of anti-HIV-1 IgM monoclonal antibodies, from a combinatorial Fab library derived from healthy individuals, and evaluated their protective role in inhibiting HIV-1 in vitro when passing across the human mucosal epithelial barrier. Primary HIV-1 isolates were efficiently transmitted over the tight polarized epithelial cells when added to their apical surface. Efficient inhibition of HIV-1 transmission was achieved when anti-HIV-1 IgM monoclonal antibodies were added to the basolateral side of the cells. Two of these human IgM MoAbs had the ability to neutralize HIV and reduced infection of dendritic cells in primary cervico-vaginal tissue biopsies in vitro. This indicates a potential role of natural IgM antibodies in the reduction of HIV-1 transmission in mucosal tissues and improve our understanding of how natural IgM antibodies against a neutralizing epitope could interfere with viral transmission.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2018
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:liu:diva-150271 (URN)10.1038/s41598-018-28242-y (DOI)000437413200036 ()29977063 (PubMedID)
Note

Funding Agencies|Swedish Medical Research Fund; MIIC support Fund at Linkoping University

Available from: 2018-08-17 Created: 2018-08-17 Last updated: 2019-05-21
Younis, S., Kamel, W., Falkeborn, T., Wang, H., Yu, D., Daniels, R., . . . Andersson, L. (2018). Multiple nuclear-replicating viruses require the stress-induced protein ZC3H11A for efficient growth. Proceedings of the National Academy of Sciences of the United States of America, 115(6), E3808-E3816
Open this publication in new window or tab >>Multiple nuclear-replicating viruses require the stress-induced protein ZC3H11A for efficient growth
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2018 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, no 6, p. E3808-E3816Article in journal (Refereed) Published
Abstract [en]

The zinc finger CCCH-type containing 11A (ZC3H11A) gene encodes a well-conserved zinc finger protein that may function in mRNA export as it has been shown to associate with the transcription export (TREX) complex in proteomic screens. Here, we report that ZC3H11A is a stress-induced nuclear protein with RNA-binding capacity that localizes to nuclear splicing speckles. During an adenovirus infection, the ZC3H11A protein and splicing factor SRSF2 relocalize to nuclear regions where viral DNA replication and transcription take place. Knockout (KO) of ZC3H11A in HeLa cells demonstrated that several nuclear-replicating viruses are dependent on ZC3H11A for efficient growth (HIV, influenza virus, herpes simplex virus, and adenovirus), whereas cytoplasmic replicating viruses are not (vaccinia virus and Semliki Forest virus). High-throughput sequencing of ZC3H11A–cross-linked RNA showed that ZC3H11A binds to short purine-rich ribonucleotide stretches in cellular and adenoviral transcripts. We show that the RNA-binding property of ZC3H11A is crucial for its function and localization. In ZC3H11A KO cells, the adenovirus fiber mRNA accumulates in the cell nucleus. Our results suggest that ZC3H11A is important for maintaining nuclear export of mRNAs during stress and that several nuclear-replicating viruses take advantage of this mechanism to facilitate their replication.

Place, publisher, year, edition, pages
Washington, United States: National Academy of Sciences, 2018
Keywords
ZC3H11A, mRNA export, stress response, virus infection
National Category
Cell Biology
Identifiers
urn:nbn:se:liu:diva-146265 (URN)10.1073/pnas.1722333115 (DOI)000430191900026 ()29610341 (PubMedID)
Note

Funding agencies: Knut and Alice Wallenberg Foundation; Swedish Cancer Society

Available from: 2018-04-05 Created: 2018-04-05 Last updated: 2019-05-21Bibliographically approved
Falkeborn, T., Asahara, N., Hayashi, M., Arai, M., Hinkula, J. & Maltais, A.-K. (2015). Comparison of the mucosal adjuvant Endocine™ with two well-known adjuvants: cholera toxin and alum. Jacobs Journal of Vaccine and Vaccination, 1(1), Article ID 006.
Open this publication in new window or tab >>Comparison of the mucosal adjuvant Endocine™ with two well-known adjuvants: cholera toxin and alum
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2015 (English)In: Jacobs Journal of Vaccine and Vaccination, ISSN 2381-2664, Vol. 1, no 1, article id 006Article in journal (Refereed) Published
Abstract [en]

To enable efficient mucosal vaccination with split or subunit antigens, an adjuvant is often needed. To date, no mucosal adjuvants are approved for human use, however, there are a variety of mucosal adjuvants in development, including the liposome-based adjuvant Endocine™. The aim of this study was to evaluate split influenza antigens together with Endocine™ and in order to assess the potency of Endocine™, the induction of humoral immune responses were compared to those following influenza vaccination with cholera toxin (CT) or aluminum salt (alum). We show that Endocine™ significantly enhances influenza-specific immune responses in intranasally immunized mice compared to nonadjuvanted vaccine. Furthermore, vaccines adjuvanted with Endocine™ evoked comparable serum IgG and virus neutralizing (VN) antibody titers as nasal vaccines adjuvanted with CT. Compared to parenteral vaccination with alum, Endocine™ triggered significantly higher mucosal and serum IgA titers, and similar VN titers. Taken together, these results support further development of Endocine™ as a mucosal adjuvant and as part of a nasal influenza vaccine candidate.

Place, publisher, year, edition, pages
Jacobs Publishers, 2015
Keywords
Mucosal adjuvant; nasal immunization; vaccine; Endocine; influenza; neutralizing antibodies
National Category
Clinical Laboratory Medicine Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-117979 (URN)
Available from: 2015-05-19 Created: 2015-05-19 Last updated: 2018-01-11Bibliographically approved
Falkeborn, T. (2015). Nasal vaccination using novel mucosal adjuvants: with main focus on influenza A virus. (Doctoral dissertation). Linköping: Linköping University Electronic Press
Open this publication in new window or tab >>Nasal vaccination using novel mucosal adjuvants: with main focus on influenza A virus
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Influenza viruses have sporadically caused pandemics during the last century, with the most severe occurring in 1918 when the “Spanish flu”, an A/H1N1 influenza virus, passed around the globe killing about 20-100 million people. Today 250 000-500 000 deaths occur annually due to influenza virus or secondary infection after influenza, e.g. pneumonia. Influenza viruses cause severe infections in susceptible age groups like children and elderly and in individuals with impaired immune response due to other medical conditions. The best way to prevent an influenza epidemic is by vaccination. Since the 1950´s we have vaccines against seasonal flu, but vaccine efficacy is not 100 % and there is a need to develop better and more effective vaccines, especially for the risk groups. Since the virus enters the host through the nasal cavity, nasal vaccination is a good approach. By stimulating a mucosal immune response already in the nasal cavity, the goal with nasal vaccination is to stop the virus before it enters the host. Nasal vaccination also reduces the risk of transmission of blood-borne diseases, and is less painful and easier to administer, compared to injectable vaccines.

In order to be able to use less immunogenic antigens, like split and subunit antigens, as nasal vaccine components, an adjuvant is needed to enhance the immune response. At the moment there is no licensed mucosal adjuvant for human use. Several studies are ongoing, but it is a complicated and long way to reach the market. In this thesis nasal vaccination with influenza antigen together with the mucosal adjuvant Endocine™ and other mucosal adjuvants has been evaluated. The Endocine™ adjuvant has been shown to be safe and well tolerated in clinical trials. Depending on the pathogen of interest, different approaches are necessary. For HIV, DNA-vaccination has been evaluated together with a plasmid encoding Salmonella typhimurium flagellin C and the mucosal adjuvant N3. The results found in paper I-IV show that by adding adjuvant to the antigen enhances the protective immune response towards the antigen. Enhanced systemic, mucosal and cell-mediated immunity were observed. Hopefully in the future these adjuvants evaluated in this thesis, will be used in vaccines for humans.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2015. p. 57
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1460
National Category
Biochemistry and Molecular Biology Immunology in the medical area
Identifiers
urn:nbn:se:liu:diva-117981 (URN)10.3384/diss.diva-117981 (DOI)978-91-7519-060-0 (ISBN)
Public defence
2015-05-28, Eken, Campus US, Linköping, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2015-05-19 Created: 2015-05-19 Last updated: 2019-11-15Bibliographically approved
Nyström, S., Bråve, A., Falkeborn, T., Devito, C., Rissiek, B., Johansson, D. X., . . . Applequist, S. E. (2013). DNA-Encoded Flagellin Activates Toll-Like Receptor 5 (TLR5), Nod-like Receptor Family CARD Domain-Containing Protein 4 (NRLC4), and Acts as an Epidermal, Systemic, and Mucosal-Adjuvant. Vaccines, 1(4), 415-443
Open this publication in new window or tab >>DNA-Encoded Flagellin Activates Toll-Like Receptor 5 (TLR5), Nod-like Receptor Family CARD Domain-Containing Protein 4 (NRLC4), and Acts as an Epidermal, Systemic, and Mucosal-Adjuvant
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2013 (English)In: Vaccines, ISSN 2076-393X, Vol. 1, no 4, p. 415-443Article in journal (Refereed) Published
Abstract [en]

Eliciting effective immune responses using non-living/replicating DNA vaccines is a significant challenge. We have previously shown that ballistic dermal plasmid DNA-encoded flagellin (FliC) promotes humoral as well as cellular immunity to co-delivered antigens. Here, we observe that a plasmid encoding secreted FliC (pFliC(-gly)) produces flagellin capable of activating two innate immune receptors known to detect flagellin; Toll-like Receptor 5 (TLR5) and Nod-like Receptor family CARD domain-containing protein 4 (NRLC4). To test the ability of pFliC(-gly) to act as an adjuvant we immunized mice with plasmid encoding secreted FliC (pFliC(-gly)) and plasmid encoding a model antigen (ovalbumin) by three different immunization routes representative of dermal, systemic, and mucosal tissues. By all three routes we observed increases in antigen-specific antibodies in serum as well as MHC Class I-dependent cellular immune responses when pFliC(-gly) adjuvant was added. Additionally, we were able to induce mucosal antibody responses and Class II-dependent cellular immune responses after mucosal vaccination with pFliC(-gly). Humoral immune responses elicited by heterologus prime-boost immunization with a plasmid encoding HIV-1 from gp160 followed by protein boosting could be enhanced by use of pFliC(-gly). We also observed enhancement of cross-clade reactive IgA as well as a broadening of B cell epitope reactivity. These observations indicate that plasmid-encoded secreted flagellin can activate multiple innate immune responses and function as an adjuvant to non-living/replicating DNA immunizations. Moreover, the capacity to elicit mucosal immune responses, in addition to dermal and systemic properties, demonstrates the potential of flagellin to be used with vaccines designed to be delivered by various routes.

Place, publisher, year, edition, pages
Basel, Switzerland: MDPI AG, 2013
Keywords
adaptive immunity; DNA adjuvant; flagellin; NLRC4; TLR5
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-99352 (URN)10.3390/vaccines1040415 (DOI)
Available from: 2013-10-16 Created: 2013-10-16 Last updated: 2015-05-19Bibliographically approved
Falkeborn, T., Brave, A., Larsson, M., Åkerlind, B., Schroder, U. & Hinkula, J. (2013). Endocine™, N3OA and N3OASq; Three Mucosal Adjuvants That Enhance the Immune Response to Nasal Influenza Vaccination. PLoS ONE, 8(8)
Open this publication in new window or tab >>Endocine™, N3OA and N3OASq; Three Mucosal Adjuvants That Enhance the Immune Response to Nasal Influenza Vaccination
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2013 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 8Article in journal (Refereed) Published
Abstract [en]

Annual outbreaks of seasonal influenza are controlled or prevented through vaccination in many countries. The seasonal vaccines used are either inactivated, currently administered parenterally, or live-attenuated given intranasally. In this study three mucosal adjuvants were examined for the influence on the humoral (mucosal and systemic) and cellular influenza A-specific immune responses induced by a nasally administered vaccine. We investigated in detail how the anionic Endocine™ and the cationic adjuvants N3OA and N3OASq mixed with a split inactivated influenza vaccine induced influenza A-specific immune responses as compared to the vaccine alone after intranasal immunization. The study showed that nasal administration of a split virus vaccine together with Endocine™ or N3OA induced significantly higher humoral and cell-mediated immune responses than the non-adjuvanted vaccine. N3OASq only significantly increased the cell-mediated immune response. Furthermore, nasal administration of the influenza vaccine in combination with any of the adjuvants; Endocine™, N3OA or N3OASq, significantly enhanced the mucosal immunity against influenza HA protein. Thus the addition of these mucosal adjuvants leads to enhanced immunity in the most relevant tissues, the upper respiratory tract and the systemic circulation. Nasal influenza vaccination with an inactivated split vaccine can therefore provide an important mucosal immune response, which is often low or absent after traditional parenteral vaccination.

Place, publisher, year, edition, pages
Public Library of Science, 2013
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-97667 (URN)10.1371/journal.pone.0070527 (DOI)000323124000019 ()
Note

Funding Agencies|Eurocine Vaccines||Vinnova Research funds||Halsofonden||

Available from: 2013-09-19 Created: 2013-09-19 Last updated: 2017-12-06
Chang, C.-H., Hinkula, J., Loo, M., Falkeborn, T., Li, R., Cardillo, T. M., . . . Wahren, B. (2012). A Novel Class of Anti-HIV Agents with Multiple Copies of Enfuvirtide Enhances Inhibition of Viral Replication and Cellular Transmission In Vitro. PLoS ONE, 7(7), e41235-e41235
Open this publication in new window or tab >>A Novel Class of Anti-HIV Agents with Multiple Copies of Enfuvirtide Enhances Inhibition of Viral Replication and Cellular Transmission In Vitro
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2012 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 7, p. e41235-e41235Article in journal (Refereed) Published
Abstract [en]

We constructed novel HIV-1 fusion inhibitors that may overcome the current limitations of enfuvirtide, the first such therapeutic in this class. The three prototypes generated by the Dock-and-Lock (DNL) technology to comprise four copies of enfuvirtide tethered site-specifically to the Fc end of different humanized monoclonal antibodies potently neutralize primary isolates (both R5-tropic and X4-tropic), as well as T-cell-adapted strains of HIV-1 in vitro. All three prototypes show EC50 values in the subnanomolar range, which are 10- to 100-fold lower than enfuvirtide and attainable whether or not the constitutive antibody targets HIV-1. The potential of such conjugates to purge latently infected cells was also demonstrated in a cell-to-cell viral inhibition assay by measuring their efficacy to inhibit the spread of HIV-1LAI from infected human peripheral blood mononuclear cells to Jurkat T cells over a period of 30 days following viral activation with 100 nM SAHA (suberoylanilide hydroxamic acid). The IgG-like half-life was not significantly different from that of the parental antibody, as shown by the mean serum concentration of one prototype in mice at 72 h. These encouraging results provide a rationale to develop further novel anti-HIV agents by coupling additional antibodies of interest with alternative HIV-inhibitors via recombinantly-produced, self-assembling, modules.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-80201 (URN)10.1371/journal.pone.0041235 (DOI)000306687700058 ()
Available from: 2012-08-22 Created: 2012-08-22 Last updated: 2017-12-07
Ahlen, G., Chen, A., Roe, B., Falkeborn, T., Frelin, L., Hall, W. W., . . . Soderholm, J. (2012). Limited effect on NS3-NS4A protein cleavage after alanine substitutions within the immunodominant HLA-A2-restricted epitope of the hepatitis C virus genotype 3a non-structural 3/4A protease. Journal of General Virology, 93, 1680-1686
Open this publication in new window or tab >>Limited effect on NS3-NS4A protein cleavage after alanine substitutions within the immunodominant HLA-A2-restricted epitope of the hepatitis C virus genotype 3a non-structural 3/4A protease
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2012 (English)In: Journal of General Virology, ISSN 0022-1317, E-ISSN 1465-2099, Vol. 93, p. 1680-1686Article in journal (Refereed) Published
Abstract [en]

It has been well established that immunological escape mutations within the hepatitis C virus genotype (gt) la non-structural (NS) 3/4A protease are partly prevented by a reduction in viral protease fitness. Surprisingly little is known about whether similar mutations affect proteases from other genotypes. In the present study, we assessed both the HLA-A2-restricted CTL response and gt3a NS3/4A protease fitness. Similar to gt1, the 1073-1081 epitope was immunodominant within the gt3a-specific HLA-A2-restricted CTL response, despite sequence similarity of only 56% between the gt1a and gt3a genes. However, unlike the gt1a NS3/4A protease, all residues within the gt3a 1073-1081 epitope could be replaced sequentially by alanine while retaining protease activity, at least in part.

Place, publisher, year, edition, pages
Society for General Microbiology, 2012
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-81827 (URN)10.1099/vir.0.043745-0 (DOI)000307746100007 ()
Note

Funding Agencies|Swedish Science Council||Swedish Cancer Society||Vinnova||Goljes Memorial Fund||Karolinska Institutet/Sodertorns University||Swedish Research Council|K2012-99X-22017-01-3|Swedish Society of Medicine||Ake Wiberg Foundation||Royal Swedish Academy of Sciences||Ruth and Richard Juhlin Foundation||Karolinska Institutet||Wilhelm and Martina Lundgren Foundation||

Available from: 2012-09-25 Created: 2012-09-24 Last updated: 2017-12-07
Sundén, B., Larsson, M., Falkeborn, T., Paues, J., Forsum, U., Lindh, M., . . . Serrander, L. (2011). Real-time PCR detection of Human Herpesvirus 1-5 in patients lacking clinical signs of a viral CNS infection. BMC Infectious Diseases, 11(220)
Open this publication in new window or tab >>Real-time PCR detection of Human Herpesvirus 1-5 in patients lacking clinical signs of a viral CNS infection
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2011 (English)In: BMC Infectious Diseases, ISSN 1471-2334, E-ISSN 1471-2334, Vol. 11, no 220Article in journal (Refereed) Published
Abstract [en]

BACKGROUND:

Infections of the central nervous system (CNS) with herpes- or enterovirus can be self-limiting and benign, but occasionally result in severe and fatal disease. The polymerase chain reaction (PCR) has revolutionized the diagnostics of viral pathogens, and by multiple displacement amplification (MDA) prior to real-time PCR the sensitivity might be further enhanced. The aim of this study was to investigate if herpes- or enterovirus can be detected in cerebrospinal fluid (CSF) from patients without symptoms.

METHODS:

Cerebrospinal fluid (CSF) samples from 373 patients lacking typical symptoms of viral CNS infection were analysed by real-time PCR targeting herpesviruses or enteroviruses with or without prior MDA.

RESULTS:

In total, virus was detected in 17 patients (4%). Epstein-Barr virus (EBV) was most commonly detected, in general from patients with other conditions (e.g. infections, cerebral hemorrhage). MDA satisfactorily amplified viral DNA in the absence of human nucleic acids, but showed poor amplification capacity for viral DNA in CSF samples, and did not increase the sensitivity for herpes virus-detection with our methodology.

CONCLUSIONS:

Viral pathogens are rarely detected in CSF from patients without signs of CNS infection, supporting the view that real-time PCR is a highly specific method to detect symptomatic CNS-infection caused by these viruses. However, EBV may be subclinically reactivated due to other pathological conditions in the CNS.

Place, publisher, year, edition, pages
BioMed Central, 2011
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-71558 (URN)10.1186/1471-2334-11-220 (DOI)000295288300001 ()21849074 (PubMedID)
Note

Funding Agencies|Linkoping University|ALF: LIO-17791 |

Available from: 2011-10-21 Created: 2011-10-21 Last updated: 2018-03-26
Falkeborn, T., Hinkula, J., Lindberg, A. & Maltais, A.-K.The mucosal adjuvant 1 Endocine™ increases immune responses to influenza antigen in aged mice.
Open this publication in new window or tab >>The mucosal adjuvant 1 Endocine™ increases immune responses to influenza antigen in aged mice
(English)Manuscript (preprint) (Other academic)
Abstract [en]

More effective influenza vaccines for the elderly population is needed. The vaccines used today are less effective in elderly compared to in adults. It is more difficult to stimulate a protective immune response in elderly due to immunosenescence. Elderly people have a decline in both humoral and cell mediated immunity, which make them more susceptible to viral infections. The aim of this study was to evaluate the mucosal adjuvant Endocine™ together with split influenza antigen in different ages of BALB/c mice (15, 20 and 25 months old). The results from this study show that a nasal influenza vaccine  formulated with Endocine™ enhanced both systemic and mucosal immune responses compared to an unadjuvanted vaccine delivered subcutaneously or intra nasal in aged mice. However, in the 25 months old mice only a very modest immune response was detected. Although the influenza-specific immune responses in aged mice were not induced to the same levels as achieved in young mice, the results show that nasal vaccine formulated with Endocine™ could provide benefits for the elderly.

National Category
Clinical Laboratory Medicine Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-117980 (URN)
Available from: 2015-05-19 Created: 2015-05-19 Last updated: 2018-01-11Bibliographically approved
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